3-Amino, 4-thio-substituted, 5-sulphamyl-benzoic acid derivatives

ABSTRACT

This invention relates to new, therapeutically active compounds of the general formula ##SPC1## 
     In which A represents one of the groupings ##EQU1## R 2  --O--, R 2  --S--, R 2  --OS--, and R 2  --O 2  S--, R 1 , R 2 , R 3 , and R 4  each represents hydrogen, an aliphatic radical, a cycloaliphatic radical, or an aromatically, cycloaliphatically, or heterocyclically substituted aliphatic radical, in addition to which R 2  and R 3  may each represent an aromatic or heterocyclic radical, and when A is ##EQU2## R 1  and R 2  may be linked to form a 5- to 8-membered heterocyclic ring system, which may have one or more nitrogen atoms, sulphur atoms, or oxygen atoms in addition to the nitrogen atom linked to R 1  and R 2  ; R 5  is hydrogen or lower alkyl; and R 6  is hydrogen or lower alkyl or acyl; to salts, esters, and amides of the said compounds; and to methods for the production of the compounds.

This is a division of application Ser. No. 887,409, filed Dec. 22, 1969,now U.S. Pat. No. 3,806,534, issued Apr. 23, 1974.

This invention relates to a series of new compounds, and to methods forthe production of the compounds.

The new compounds have the general formula ##SPC2##

In which A stands for ##EQU3## R² --O--, R² --S--, R² --OS--, or R² --O₂S--, and R¹, R², R³, and R⁴ each represents an aliphatic radical, acycloaliphatic radical, or an aromatically, cycloaliphatically orheterocyclically substituted aliphatic radical; in addition R² and R³may each represent an aromatic or heterocyclic radical; and when A is##EQU4## R¹ and R² together with the nitrogen atom can represent aheterocyclic ring system with from 5 to 8 ring members, and which mayhave additionally one or more nitrogen, oxygen, or sulphur atoms in thering; R⁵ represents a lower alkyl radical, and R⁶ represents a loweralkyl radical or an acyl group; R¹, R³, R⁴, R⁵, and R⁶ may also be eacha hydrogen atom. The invention further comprises salts, esters, andamides of the compounds of formula I.

In particular, each of R¹, R², R³, and R⁴ may represent a straight orbranched, saturated or unsaturated, alkyl radical, e.g. a methyl, ethyl,propyl, isopropyl, butyl, isobutyl, or tert. butyl radical, or one ofthe different isomeric pentyl, hexyl, or heptyl radicals, an alkenyl oralkynyl radical, e.g. a vinyl, allyl, or propargyl radical, a cycloalkylor cycloalkenyl radical, e.g. a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, or cyclooctyl radical, or one of the differentisomeric cyclopentenyl or cyclohexenyl radicals, or an adamantylradical. The aliphatic radicals may further contain hereto atoms, e.g.oxygen, sulphur, or nitrogen which may interrupt the carbon chain, andmay be further substituted, e.g. with lower alkyl radicals. In thearomatically, cycloaliphatically or heterocyclically substitutedaliphatic radicals, the aromatic part of the radical can be a mono- orbicyclic aryl radical, e.g. a phenyl or naphthyl radical, thecycloaliphatic part of the radical can be one of the cycloalkyl orcycloalkenyl radicals mentioned above, the heterocyclic part of theradical can be a mono- or bicyclic radical containing one or moreoxygen, sulphur, and nitrogen atoms as ring members, e.g. 2-, 3-, or4-pyridyl, 2- or 3-furyl or -thienyl, thiazolyl, imidazolyl,benzimidazolyl, and the corresponding hydrogenated ring systems, and thealiphatic part of the radicals can contain 1 to 4 carbon atoms.Illustrative examples of such aromatically or heterocyclicallysubstituted aliphatic radicals are benzyl, 1- or 2-phenylethyl, 1- or2-naphthyl-methyl, furyl-methyl, and the corresponding ethyl, propyl,and butyl radicals. When, additionally, R² and R³ represent aromatic orheterocyclic radicals these can be the mono- or bicyclic radicalsalready mentioned above.

When A represents ##EQU5## and R¹ and R² together with the nitrogen atomrepresent a heterocyclic ring system, this stands particularly for asaturated or unsaturated heterocyclic ring optionally containing one ormore nitrogen, oxygen, or sulphur atoms, such as piperidyl, morpholinyl,thiomorpholinyl, pyrrolidyl, imidazolyl, thiazolidyl, piperazinyletcetera radicals. When R⁶ represents an acyl group, it is preferably alower aliphatic acyl group, e.g. an acetyl or propionyl group.

All the above mentioned radicals can be substituted in differentpositions with different groups, such as one or more halogen atoms, e.g.chlorine or bromine atoms, with an alkyl or halo-alkyl group, e.g.trifluoromethyl, with carboxy, carbalkoxy, or carbamyl radicals,di-lower alkylamino radicals, or hydroxy groups, which may be etherifiedor esterified, with etherified mercapto groups, or with sulphonamidegroups.

The salts of the compounds of the invention are pharmaceuticallyacceptable salts, and include, for example, alkali metal salts, alkalineearth metal salts, the ammonium salt, or amine salts formed, forinstance, from mono-, di-, or trialkylamines, from mono-, di-, ortrialkanolamines, or from cyclic amines. The esters of the compounds arepreferably derived from substituted or unsubstituted lower aliphaticalcohols, phenols, or aralkyl alcohols, e.g. the methyl ester, thecyanomethyl ester, the phenyl ester, and the benzyl ester.

The compounds of the invention possess valuable therapeutic propertiesand have, according to animal experiments performed in connection withthe present invention, a particularly strong effect as diuretics andsaluretics, the ratio between the excretion of sodium ions and potassiumions being very favourable. Furthermore the compounds are notcarboanhydrase inhibitors, and these facts in connection with thefavourable therapeutic index and a low toxicity make the presentcompounds particularly valuable.

The effect of the present compounds is surprising in respect to thedisclosure in the specification of our Belgian Patent No. 716,122 as itwas not to be foreseen that the halogen substituent in the neighbouringposition to the sulphonamide group could be replaced with the resultthat compounds with even stronger activity were obtained.

Illustrative examples of compounds of formula I having a particularlystrong effect are compounds where A is as defined above and where R¹,R³, and R⁵ are hydrogen, R² is a substituted or unsubstituted phenylgroup, R⁴ is an alkyl radical having from 3 to 6 carbon atoms, or abenzyl, furfuryl, or thienylmethyl radical, R⁶ is hydrogen, a methylgroup or lower aliphatic acyl group, and the methyl esters of thesecompounds.

The present compounds are effective after oral, enteral or parenteraladministration, and for therapeutic purposes they are preferablyformulated as tablets, pills, dragees, or capsules containing the freeacid of salts thereof with atoxic bases, or the esters or amidesthereof, mixed with carriers and/or auxiliary agents.

Pharmaceutical organic or inorganic, solid or liquid carriers suitablefor oral, enteral, or parenteral administration can be used to make upcompositions containing the present compounds. Gelatine, lactose,starch, magnesium stearate, talc, vegetable and animal fats and oils,gum, polyalkylene glycol, or other known carriers for medicaments areall suitable as carriers.

The compositions may further contain other therapeutic compounds appliedin the treatment of, for example oedemas and hypertension, besides thewell known auxiliary agents. Such other compounds may be, for instance,Veratrum- or Rauwolfia alkaloids, e.g. reserpine, rescinnamine, orprotoveratrine, or synthetic hypotensive compounds, e.g. hydralazine, orother diuretics and saluretics, such as the well-knownbenzothiadiazines, e.g. hydroflumethiazide, bendroflumethiazide, and thelike. Potassium-sparing diuretics, e.g. triamterene, may also be used inthe preparation of the compositions. For some purposes it may bedesirable to add small amounts of carboanhydrase inhibitors oraldosterone antagonists, e.g. spironolactone.

Salts, which are soluble in water, may with advantage be administered byinjection. The pharmaceutical preparations are useful in the treatmentof oedematous conditions, e.g. cardiac, hepatic, renal, lung and brainoedema, or oedematous conditions during pregnancy, in the treatment ofpathological conditions which produce an abnormal retention of theelectrolytes of the body, and in the treatment of hypertension.

Another object of the invention resides in the selection of a dose ofone of the new compounds, and its salts which can be administered sothat the desired activity is achieved without simultaneous secondaryeffects. It has been found that the compounds and their salts areconveniently administered in dosage units containing not less than 0.1mg, and up to 25 mg, preferably from 0.25 to 2.5 mg, calculated as thefree acid of formula I.

By the term "dosage unit" is meant a unitary, i.e. a single dose whichis capable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically stable unit dosecomprising either the active material as such or a mixture of it withsolid or liquid pharmaceutical diluents or carriers.

If the composition is to be injected, a sealed ampoule, a vial or asimilar container may be provided containing a parenterally acceptableaqueous or oily injectable solution or dispersion of the active materialas the dosage unit.

The parenteral preparations are useful in particular in the treatment ofconditions where a quick dehydration is desirable, e.g. in the intensivetherapy applied in the case of oedemas in the lung. In the continuoustherapy of patients suffering from e.g. hypertension, the tablets orcapsules may be the appropriate form of pharmaceutical preparation owingto the prolonged effect obtained when the drug is given orally, inparticular in the form of sustained-release tablets.

In the treatment of heart failure and hypertension, such tablets mayadvantageously contain other active components, as specifiedhereinbefore.

The present compounds may be provided by various methods. In oneembodiment of the invention a compound of the general formula ##SPC3##

in which A, R³, and R⁶ are as hereinbefore defined, or a salt, an ester,or an amide thereof, is subjected to a reduction, for example bycatalytic hydrogenation using a noble metal catalyst, to yield thecompounds of the invention, in which R⁴ and R⁵ are hydrogen atoms. Insome cases, for instance when the substituents would be affected by acatalytic hydrogenation, other reducing agents, such as sodiumdithionite or metallic iron, may be preferred. The compounds soobtained, preferably in the form of a salt or an ester, can bemonoalkylated by reaction with a compound of the formula R⁴ X, R⁴ beingas defined hereinbefore, and X being a halogen atom, preferably chlorineor bromine, a hydroxyl group, or a sulphonyloxy group, an alkyl- oraryl-sulphonyloxy group, the carboxylic acid group subsequently beingliberated, if desired. The R⁵ group can subsequently be introduced by anordinary alkylation process or by a reductive alkylation in knownmanner.

In another embodiment, a 3-amino-4-A-5-R³ R⁶ -sulphamylbenzoic acid oran ester or amide thereof is subjected to reductive alkylation, using inthe reaction an aldehyde, which is capable of introducing thecorresponding R⁴ substituent; on the other hand the esters and amidescan be prepared as the last step from the carboxylic acid of formula I,and the R⁶ -substituent may be introduced as an intermediary step, or asa last step.

The different steps of the process are standard procedures includingreductive alkylation, hydrogenation, esterification, amidation, using areactive derivative of the corresponding carboxylic acid, or hydrolysis,and the reaction conditions may vary according to the starting productsand the substituents of the reacting compounds. The compounds areobtained in free form or in form of their salts, esters or amidesdepending upon the conditions under which the reaction is performed.

The starting material of formula IV is prepared according to thefollowing reaction scheme: ##SPC4##

in which formulae A and R³ have the meanings before defined and R⁶ is alower alkyl, the compound III being used either as the free carboxylicacid or in the form of a salt, or an ester, in which latter case thecompound IV is also obtained as an ester, which, if desired, may behydrolyzed. In the case, where R⁶ is an acyl group, the compounds offormula IV can be provided by acylation of the corresponding compoundsin which R⁶ is hydrogen.

If desired, the carboxylic acid group of the compounds of formula IV canbe amidated using a reactive derivative thereof, e.g. an acid halide.

The starting materials of formula II and of formula III, in which R³ andR⁶ are hydrogen atoms, are described in the specification of our BelgianPatent No. 716,122.

The N-substituted sulphamyl derivatives of formula III are generallyprepared by treating a compound of formula II with an amine ##EQU6## R³being different from hydrogen, and R⁶ being an alkyl group or hydrogen,preferably under mild conditions, i.e. at low temperature and without anexcess of the amine ##EQU7## and usually in the presence of a base whichis not capable of being alkylated and which is used as an acceptor forthe acid liberated by the process.

The reaction product of formula III, or an ester or an amide thereof, istreated with a compound of the formula A-H, A being as defined above,i.e. with an amine, an alcohol, a thioalcohol, a phenol, a thiophenol,or a sulphinic acid to form a compound of formula IV, or thecorresponding ester. In the case where A stands for ##EQU8## A-H is usedin the reaction if the form of the free amine, in the case where Astands for R² --O--, R.sup. 2 --S--, or R² --O₂ S--, reaction conditionsare used in which the ionic form of A is present or in which A is analcoholate, thioalcoholate, phenolate, or thiophenolate, or asulphinate, respectively. Water, ethanol, aqueous alcohols, or alcoholsof the formula R² --OH--, wherein R² is as hereinbefore defined, as wellas other suitable solvents may, if desired, be used as reaction media inthis process, and the reaction temperature depends on the reactantsused.

In the case where A stands for ##EQU9## and is identical with ##EQU10##the compound of formula II can be transformed in one step into acompound of formula IV, using not less than two equivalents of the amine##EQU11##

The compounds of formula IV, A being R² --S--, can furthermore beconverted to the corresponding sulphinyl or sulphonyl derivatives byoxidation, e.g. with hydrogen peroxide, the amount of peroxide and thereaction conditions being decisive for the degree of oxidation,whereafter the compounds of formula I can be obtained as describedabove.

In another embodiment of the method for the preparation of the compoundsof the invention in which A stands for R² --OS-- and R² --O₂ S--, thecompounds can also be and are preferably prepared from the correspondingcompounds of formula I in which A is R² --S-- by oxidation with, forinstance, hydrogen peroxide. Depending upon the amount of hydrogenperoxide and the reaction conditions used, the oxidation results in thesulphinyl or the sulphonyl derivatives. These oxidations can beperformed on the free carboxylic acids as well as on salts, on esters,or on amides thereof. In the case where a carboxylic acid derivative isobtained, the free carboxylic acid may be liberated subsequently bywell-known processes, if desired. Compounds of the invention, in whichthe substituents are unsaturated, may be hydrogenated or transformed byaddition-reactions into other compounds of the invention, and furthersubstituents in R² and in R⁴ may be introduced or removed on anyreaction step.

The invention will now be described by the following examples which areonly illustrative and are not to be limiting:

EXAMPLE 1 3-Amino-4-phenoxy-5-sulphamyl-benzoic acid

A. 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (140 g), phenol(100 g), sodium bicarbonate (170 g), and water (1000 ml) was heated to85°C while stirring and kept at this temperature for 16 hours. Aftercooling to 4°C, the precipitated sodium salt of3-nitro-4-phenoxy-5-sulphamyl-benzoic acid was filtered off and washedwith ice-water. The sodium salt was dissolved in boiling water (3000ml), and the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid was precipitatedby the addition of 4N hydrochloric acid. After cooling, the acid wasisolated by suction and dried. The melting point was 255°-256°C.

B. 3-amino-4-phenoxy-5-sulphamyl-benzoic acid

A suspension of 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid (20 g) inwater (100 ml) was adjusted to a pH of 8 by the addition of 1N lithiumhydroxide. The resulting solution was hydrogenated at room temperatureand 1.1 atmosphere hydrogen pressure, using a palladium-on-carboncatalyst (0.6 g catalyst containing 10% pd). After the hydrogen uptakehad become negligible, the catalyst was removed by filtration, and the3-amino- 4-phenoxy-5-sulphamyl-benzoic acid was precipitated from thefiltrate by the addition of 4N hydrochloric acid until the pH was 2.5.After recrystallization from aqueous ethanol and drying, the meltingpoint was 255°-256°C.

EXAMPLE 2 3-Amino-5-methylsulphamyl-4-phenoxy-benzoic acid

A. 5-methylsulphamyl-3-nitro-4-phenoxy-benzoic acid

By substituting 4-chloro-5-methylsulphamyl-3-nitro-benzoic acid (147 g)for 4-chloro-3-nitro-5-sulphamyl-benzoic acid and following theprocedure of Example 1 A, the above 3-nitro-compound was obtained with amelting point of 219°-222°C.

The above starting material is new and was prepared in the followingmanner:

To a mixture of 1N sodium hydroxide (60 ml) and aqueous methylamine(3.43 g containing 1.2 g of methylamine)4-chloro-5-chlorosulphonyl-3-nitro-benzoic acid (9.3 g) was added inportions, while stirring and keeping the mixture at 0°-3°C. Then thereaction mixture was left standing until it reached room temperature,after which the 4-chloro-5-methylsulphamyl-3-nitro-benzoic acid wasprecipitated by slow acidification with 4N hydrochloric acid. Theprecipitate was collected by suction and recrystallized from aqueousethanol. The melting point was 228°-229°C.

B. 3-amino-5-methylsulphamyl-4-phenoxy-benzoic acid

By substituting 5-methylsulphamyl-3-nitro-4-phenoxy-benzoic acid for3-nitro-4-phenoxy-5-sulphamyl-benzoic acid and following the procedureof Example 1 B, the above compound was obtained with a melting point of283°C.

EXAMPLE 3 3-Amino-5-dimethylsulphamyl-4-phenoxy-benzoic acid

A. 5-dimethylsulphamyl-3-nitro-4-phenoxy-benzoic acid

A mixture of 4-chloro-5-dimethylsulphamyl-3-nitro-benzoic acid (3.08 g),phenol (2 g), sodium hydrogen carbonate (3.4 g), and water (20 ml) washeated at 90°C for 8 hours. Then water (40 ml) was added and, aftercooling, the 5-dimethylsulphamyl-3-nitro-4-phenoxy-benzoic acid wasprecipitated by acidification with 4N hydrochloric acid. After isolationby filtration and several recrystallizations from ethanol, the saidcompound was obtained with a melting point of 224°-226°C.

B. 3-amino-5-dimethylsulphamyl-4-phenoxy-benzoic acid

Following the procedure of Example 1 B and substituting5-dimethylsulphamyl-3-nitro-4-phenoxy-benzoic acid for3-nitro-4-phenoxy-5-sulphamyl-benzoic acid, the above compound wasobtained with a melting point of 211°-212°C.

By substituting 5-n-butylsulphamyl-4-chloro-3-nitro-benzoic acid (3.36g) for the 4-chloro-5-dimethylsulphamyl-3-nitro-benzoic acid of Example3 A, 5-n-butylsulphamyl-3-nitro-4-phenoxy-benzoic acid was obtained witha melting point of 191°-192°C.

By substituting 5-n-butylsulphamyl-3-nitro-4-phenoxy-benzoic acid for3-nitro-4-phenoxy-5-sulphamyl-benzoic acid in Example 1 B,3-amino-5-n-butylsulphamyl-5-phenoxy-benzoic acid was obtained as ahemi-hydrate with a melting point of 188°-189°C.

The starting materials, 4-chloro-5-dimethylsulphamyl-3-nitro-benzoicacid and 5-n-butylsulphamyl-4-chloro-3-nitro-benzoic acid, were new andwere obtained as described for the starting material of Example 2 bysubstituting aqueous dimethylamine (3.6 g containing 1.5 g ofdimethylamine) and n-butylamine (2.2 g), respectively, for the aqueousmethylamine, and had melting points of 233°-235°C, and 196°-198°C,respectively.

EXAMPLE 4 3-Amino-4-anilino-5-phenylsulphamyl-benzoic acid and sodiumsalt

A. 4-anilino-3-nitro-5-phenylsulphamyl-benzoic acid

To a solution of 4-chloro-3-nitro-5-chlorosulphonyl-benzoic acid (6 g)in ethyl acetate (50 ml), aniline (7.5 g) was added, while stirring. Thereaction mixture was stirred for a further 8 hours and filtered. Thefiltrate was evaporated, and the residue was dissolved in a mixture ofaqueous sodium hydrogen carbonate and diethyl ether. The aqueous layerwas separated, and the 4-anilino-3-nitro-5-phenylsulphamyl-benzoic acidwas precipitated by addition of 4N hydrochloric acid. Afterrecrystallization from aqueous ethanol (25% ethanol in water), themelting point was 249°-250°C.

B. 3-amino-4-anilino-5-phenylsulphamyl-benzoic acid and sodium salt

A suspension of 4-anilino-3-nitro-5-phenylsulphamyl-benzoic acid (2 g)in water (15 ml) was adjusted to pH 8 by means of 1N sodium hydroxide,and the resulting solution was hydrogenated after addition of Pd (0.15g) on carbon powder catalyst (10%). After the hydrogen uptake had becomenegligible, the reaction mixture was heated to 95°C, and the catalystwas removed by filtration. After cooling, the precipitated sodium saltof 3-amino-4-anilino-5-phenylsulphamyl-benzoic acid was collected byfiltration.

1.5 g of the sodium salt of 3-amino-4-anilino-5-phenylsulphamyl-benzoicacid was dissolved in hot water (50 ml). 1N hydrochloric acid was addeduntil pH 2, and the mixture was cooled. The precipitated3-amino-4-anilino-5-phenylsulphamyl-benzoic acid was collected,recrystallized from aqueous methanol, and dried in vacuo at 78°C. Thecrystalline compound contained 1 molecule of water of crystallization.The melting point was 222°-223°C.

EXAMPLE 5 3-Amino-4-(p-methoxyphenoxy)-5-sulphamyl-benzoic acid

A. 4(p-Methoxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (14 g),p-methoxyphenol (9.3 g), and 1N sodium bicarbonate (200 ml) was stirredat 90°C for 5 hours. After cooling, the resulting4-(p-methoxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid was precipitatedby the addition of 4N hydrochloric acid until the pH was 1, andcollected by suction. The crude acid was dissolved in hot methanol (100ml) and precipitated by the addition of water (100 ml) and cooling.After collection and drying in vacuo, the melting point was 229°-230°C.

B. 3-amino-4-(p-methoxyphenoxy)-5-sulphamyl-benzoic acid

By substituting 4-(p-methoxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid (7g) for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B,the above compound was obtained with a melting point of 260°-261°C.

EXAMPLE 6 3-Amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid

A. 3-nitro-5-sulphamyl-4-(m-trifluoromethylphenxoy)-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (7 g),m-trifluoromethylphenol (20 g), and 1N sodium bicarbonate (100 ml) wasstirred at 95°C for 6 hours. Then the reaction mixture was acidified bythe addition of 4N hydrochloric acid and the excess oftrifluoromethylphenol was removed by steam distillation. After cooling,the precipitated3-nitro-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid wascollected by suction and recrystallized several times frommethanol-water. The melting point of the pure compound was 205°-206°C.

B. 3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid

By substituting 3-nitro-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoicacid for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B,the above compound was obtained with a melting point of 270°C.

EXAMPLE 7 3-Amino-4-(m-chlorophenoxy)-5-sulphamyl-benzoic acid

A. 4-(m-Chlorophenoxy)-3-nitro-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g),m-chlorophenol (26 g), sodium bicarbonate (34 g), and water (200 ml) wasstirred at 85°C for 10 hours. After cooling, excess m-chlorophenol wasremoved by extraction with diethyl ether, and4-(m-chlorophenoxy)-3-nitro-5-sulphamyl-benzoic acid was precipitatedfrom the aqueous layer by the addition of 4N hydrochloric acid. Afterrecrystallization from aqueous methanol, the melting point was230°-232°C.

B. 3-amino-4-(m-chlorophenoxy)-5-sulphamyl-benzoic acid

A mixture of ammonium chloride (1.2 g), metallic iron powder (11 g),concentrated hydrochloric acid (0.05 ml), and water (30 ml) was heatedon a steam bath. 4-(m-Chlorophenoxy)-3-nitro-5-sulphamyl-benzoic acid (3g) was added while stirring, and the heating was continued for 6 hours.Then 1N sodium hydroxide (50 ml) was added, and the reaction mixture wasfiltered. The filter cake was washed twice with 1N sodium hydroxide (50ml each time). The combined filtrates were adjusted to a pH of 2.5 bythe addition of 4N hydrochloric acid. After cooling, the precipitated3-amino-4-(m-chlorophenoxy)-5-sulphamyl-benzoic acid was collected bysuction, and recrystallized from aqueous ethanol. The melting point was239°-240°C.

EXAMPLE 8 3-Amino-4-methoxy-5-sulphamyl-benzoic acid

A. 4-methoxy-3-nitro-5-sulphamyl-benzoic acid (14 g) was added to asolution of sodium methoxide, prepared from sodium (6.9 g) and methanol(200 ml). The reaction mixture was refluxed for 5 hours and evaporatedin vacuo. The residue was dissolved in water (100 ml) and conc.hydrochloric acid was added (50 ml). The precipitated4-methoxy-3-nitro-5-sulphamyl-benzoic acid was recrystallized fromwater. The melting point was 200°-201°C.

B. 3-amino-4-methoxy-5-sulphamyl-benzoic acid

4-Methoxy-3-nitro-5-sulphamyl-benzoic acid (2.8 g) was dissolved in 1Nsodium hydrogen carbonate solution (12 ml), and hydrogenated, usingPd-on-carbon as a catalyst, and the3-amino-4-methoxy-5-sulphamyl-benzoic acid was isolated as described inExample 1 B. After several recrystallizations from water and drying at78°C in vacuo, the melting point was 210°C under decomposition.

EXAMPLE 9 3-Amino-4-anilino-5sulphamyl-benzoic acid

A. 4-anilino-3-nitro-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (8.4 g), aniline(8.4 g), and water (40 ml) was stirred at 80°C for 2 hours. After theaddition of 1N hydrochloric acid (50 ml) and cooling, the precipitated4-anilino-3-nitro-5-sulphamyl-benzoic acid was collected by suction,washed with water, and recrystallized from aqueous ethanol. The meltingpoint was 261°-262°C.

B. 3amino-4-anilino-5-sulphamyl-benzoic acid

A suspension of 4-anilino-3-nitro-5-sulphamyl-benzoic acid (7 g) inwater (80 ml) was adjusted to a pH of 9 by the addition of 2N sodiumhydroxide or lithium hydroxide, and the resulting solution washydrogenated at room temperature and 1.1 atmospheres hydrogen pressureafter the addition of a palladium-on-carbon catalyst (0.3 g catalystcontaining 10% Pd). After the hydrogen uptake had become negligible, thecatalyst was removed by filtration, and the3-amino-4-anilino-5-sulphamyl-benzoic acid was precipitated from thefiltrate by addition of 4N hydrochloric acid until the pH was 2.5. Afterrecrystallization from aqueous ethanol and drying in vacuo, the meltingpoint was 251°C.

EXAMPLE 10 3-Amino-5-sulphamyl-4-(m-toluidino)-benzoic acid

A. 3-nitro-5-sulphamyl-4-(m-toluidino)-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g),m-toluidine (32.2 g), and water (500 ml) was refluxed for 3 hours. Aftercooling and acidification with 2N hydrochloric acid, the precipitated3-nitro-5-sulphamyl-4-(m-toluidino)-benzoic acid was collected bysuction, washed with water, and recrystallized from isopropanol. Afterdrying at 115°C in vacuo, the melting point was 256°-259°C.

B. 3-amino-5-sulphamyl-4-(m-toluidino)-benzoic acid

By substituting 3-nitro-5-sulphamyl-4-(m-toluidino)-benzoic acid for the4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the abovecompound was obtained with a melting point of 280°-282°C afterrecrystallization from ethanol.

EXAMPLE 11 3-Amino-5-sulphamyl-4-(p-toluidino)-benzoic acid

A. 3-nitro-5-sulphamyl-4 -(p-toluidino)-benzoic acid

By substituting p-toluidine for m-toluidine in Example 10 A, the abovecompound was obtained with a melting point of 252°-253°C, afterrecrystallization from ethanol and drying.

B. 3-amino-5-sulphamyl-4-(p-toluidino)-benzoic acid

By substituting 3-nitro-5-sulphamyl-4-(p-toluidino)-benzoic acid for the4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the abovecompound was obtained with a melting point of 249°-252°C.

EXAMPLE 12 3-Amino-5-sulphamyl-4-(o-toluidino)-benzoic acid

A. 3-nitro-5-sulphamyl-4-(o-toluidino)-benzoic acid

By substituting o-toluidine for m-toluidine in Example 10 A, the abovecompound was obtained with a melting point of 251°-252°C.

B. 3-amino-5-sulphamyl-4-(o-toluidino)-benzoic acid

By substituting 3-nitro-5-sulphamyl-4-(o-toluidino)-benzoic acid for the4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the abovecompound was obtained.

EXAMPLE 13 3-Amino-4-(o-methoxyanilino)-5-sulphamyl-benzoic acid

A. 4-(o-Methoxyanilino)-3-nitro-5-sulphamyl-benzoic acid

By substituting o-anisidine (37 g) for m-toluidine in Example 10 A, theabove compound was obtained with a melting point of 207°-208°C afterrecrystallization from ethanol and drying in vacuo.

B. 3-amino-4-(o-methoxyanilino)-5-sulphamyl-benzoic acid

By substituting 4- (o-methoxyanilino)-3-nitro-5-sulphamyl-benzoic acidfor the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, theabove compound was obtained after recrystallization from aqueousethanol.

EXAMPLE 14 3-Amino-4-(m-methoxyanilino)-5-sulphamyl-benzoic acid

A. 4-(m-Methoxyanilino)-3-nitro-5-sulphamyl-benzoic acid

By substituting m-anisidine (37 g) for m-toluidine in Example 10 A, theabove compound was obtained with a melting point of 253°-254°C.

B. 3-amino-4-(m-methoxyanilino)-5-sulphamyl-benzoic acid

By substituting 4-(m-methoxyanilino)-3-nitro-5-sulphamyl-benzoic acidfor the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, theabove compound was obtained with a melting point of 232°-234°C afterrecrystallization from aqueous methanol.

EXAMPLE 15 3-Amino-4-(p-methoxyanilino)-5-sulphamyl-benzoic acid

A. 4-(p-Methoxyanilino)-3-nitro-5-sulphamyl-benzoic acid

By substituting p-anisidine (37 g) for m-toluidine in Example 10 A, theabove compound was obtained with a melting point of 246°C (decomp.).

B. 3-amino-4-(p-methoxyanilino)-5-sulphamyl-benzoic acid

By substituting 4-(p-methoxyanilino)-3-nitro-5-sulphamyl-benzoic acidfor the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, theabove compound was obtained with a melting point of 214°C.

EXAMPLE 16 3-Amino-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoic acid

A. 3-nitro-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoic acid

By substituting m-trifluoromethylaniline (49.5 g) for m-toluidine inExample 10 A and extending the reaction time to 7 hours, the abovecompound was obtained after the cooled reaction mixture had beenacidified and diluted with ethanol (150 ml). After recrystallizationfrom aqueous ethanol, the melting point was 213°-215°C.

B. 3-amino-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoic acid

By substituting 3-nitro-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoicacid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B,the above compound was obtained with a melting point of 273°-274°C.

EXAMPLE 17 3-Amino-4-(2,4-dimethyanilino)-5-sulphamyl-benzoic acid

A. 4-(2,4-dimethyanilino)-3-nitro-5-sulphamyl-benzoic acid

By substituting 2,4-dimethylaniline (36.5 g) for m-toluidine in Example10 A, the above compound was obtained with a melting point of 224°-226°Cafter recrystallization from ethanol and drying. The compoundcrystallized with one molecule of ethanol.

B. 3-amino-4-(2,4-dimethylanilino)-5-sulphamyl-benzoic acid

By substituting 3-nitro-5-sulphamyl-4-(2,4-dimethylanilino)-benzoic acidfor the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, theabove compound was obtained with a melting point of 241°-241.5°C afterrecrystallization from ethanol.

EXAMPLE 18 3-Amino-4-(p-chloroanilino)-5-sulphamyl-benzoic acid

A. 4-(p-Chloroanilino)-3-nitro-5-sulphamyl-benzoic acid

By substituting p-chloroaniline (39 g) for m-toluidine in Example 10 A,the above compound was obtained with a melting point of 241°-243°C afterrecrystallization from ethanol and drying in vacuo.

3-Amino-4-(p-chloroanilino)-5-sulphamyl-benzoic acid

A mixture of 4-(p-chloroanilino)-3-nitro-5-sulphamyl-benzoic acid (7.43g), water (50 ml), and concentrated aqueous ammonia (15 ml) was stirredat 25°C, and a solution of sodium dithionite (13.5 g) in water (50 ml)was added dropwise. After 1 hour, the pH of the reaction mixture wasadjusted to 2.5, and the precipitated reaction product was filtered off.After repeated recrystallizations from aqueous ethanol, and after dryingfor 4 hours in vacuo, 3-amino-4-(p-chloroanilino)-5-sulphamyl-benzoicacid was obtained with a melting point of 273°-274°C.

EXAMPLE 19 3-Amino-4-(p-hydroxyanilino)-5-sulphamyl-benzoic acid

A. 4-(p-Hydroxyanilino)-3-nitro-5-sulphamyl-benzoic acid

By substituting p-aminophenol (24.5 g) for m-toluidine in Example 10 A,the above compound was obtained with a melting point of 262°C (decomp.)after recrystallization from aqueous ethanol and water.

B. 3-amino-4-(p-hydroxyanilino)-5-sulphamyl-benzoic acid

By substituting 4-(p-hydroxyanilino)-3-nitro-5-sulphamyl-benzoic acid(10 g) for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1B, the above compound was obtained with a melting point of 296°C(decomp.).

EXAMPLE 20 3-Amino-4-cyclohexylamino-5-sulphamyl-benzoic acid

A. 4-cyclohexylamino-3-nitro-5-sulphamyl-benzoic acid

By substituting cyclohexylamine (30 g) for m-toluidine in Example 10 A,the above compound was obtained with a melting point of 185°-186°C afterrecrystallization from aqueous ethanol and drying in vacuo.

B. 3-amino-4-cyclohexylamino-5-sulphamyl-benzoic acid

By substituting 4-cyclohexylamino-3-nitro-5-sulphamyl-benzoic oic acid(15 g) for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1B, the above compound was obtained with a melting point of 233°C(decomp.).

EXAMPLE 21 3-Amino-4-benzylamino-5-sulphamyl-benzoic acid

A. 4-benzylamino-3-nitro-5-sulphamyl-benzoic acid

A mixture of 4-chlor-3-nitro-5-sulphamyl-benzoic acid (8.4 g),benzylamine (12.84 g), and water (40 ml) was stirred at room temperaturefor 3 hours. After standing for 30 minutes, the liquor was decanted off,water (100 ml) was added, and 4-benzylamino-3-nitro-5-sulphamyl-benzoicacid was precipitated by the addition of 4N hydrochloric acid. Aftercollection and recrystallization from aqueous methanol, the meltingpoint was 188°C (decomp.).

B. 3-amino-4-benzylamino-5-sulphamyl-benzoic acid

By substituting 4-benzylamino-3-nitro-5-sulphamyl-benzoic acid for the4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the abovecompound was obtained with a melting point of 218°-219°C afterrecrystallization from aqueous methanol.

EXAMPLE 22 3-Amino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid

A. 3-nitro-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g),β-phenylethylamine (29 g), and water (200 ml) was refluxed for 2.5hours. After cooling, the reaction mixture was adjusted to a pH of 9.5and extracted with diethyl ether. The aqueous layer was then acidifiedby addition of 4N hydrochloric acid, and the precipitated3-nitro-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid was collected bysuction. After recrystallization from aqueous ethanol, the melting pointwas 208°-208.5°C.

B. 3-amino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid

By substituting 3-nitro-4-(β-phenylethylamino)-5-sulphamyl-benzoic acidfor the 4-anilino-3-nitro-5-sulphamyl-benzoic acid Example 9 B, theabove compound was obtained with a melting point of 194°-195°C.

EXAMPLE 23 3-Amino-4-(p-carboxyanilino)-5-sulphamyl-benzoic acid

A. 4-(p-Carboxylanilino)-3-nitro-5-sulphamyl-benzoic acid

A suspension of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g) andp-aminobenzoic acid (10.95 g) in water was adjusted to a pH of 7 by theaddition of sodium bicarbonate. The resulting solution was refluxed for10 hours. After acidifying with 4N hydrochloric acid and cooling, theprecipitated 4-(p-carboxyaanilino)-3-nitro-5-sulphamyl-benzoic acid wascollected by suction and recrystallized from aqueous ethanol. Themelting point was 297°C (decomp.). The compound contained one moleculeof water of crystallization.

B. 3-amino-4-(p-carboxyanilino)-5-sulphamyl-benzoic acid

By substituting 4-(p-carboxyanilino)-3-nitro-5-sulphamyl-benzoic acidfor the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, theabove compound was obtained with a melting point of 262°C (decomp.)after drying in vacuo at 115°C.

EXAMPLE 24 3-Amino-4-(2-methoxyethylamino)-5-sulphamyl-benzoic acid

A. 4-(2methoxyethylamino)-3-nitro-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (4.2 g),2-methoxyethylamine (5.6 g), and 50% ethanol (10 ml) was heated to 60°Cfor 1 hour. The ethanol was distilled off under reduced pressure, andthe resulting 4-(2-methoxyethylamino)-3-nitro-5-sulphamyl-benzoic acidwas precipitated by addition of 4N hydrochloric acid until pH 2. Afterrecrystallization from water, the melting point was 192°-194°C. Thecompound crystallized with 1 molecule of water of crystallization.

B. 3-amino-4-(2-methoxyethylamino)- 5-sulphamyl-benzoic acid

4-(2-Methoxyethylamino)-3-nitro-5-sulphamyl-benzoic acid (3.2 g) wasdissolved in 1N sodium hydroxide (10 ml) and hydrogenated after additionof moist Raney-Nickel (1 g). When the hydrogen uptake had becomenegligible, the catalyst was removed by filtration, and the resulting3-amino-4-(2-methoxyethylamino)-5-sulphamyl-benzoic acid wasprecipitated from the filtrate by addition of 4N hydrochloric acid untilpH 3. After recrystallization from water, the melting point was209°-211°C.

EXAMPLE 25 3-Amino-4-isopropylamino-5-sulphamyl-benzoic acid

A. 4-isopropylamino-3-nitro-5-sulphamyl-benzoic acid

Isopropylamine (120 ml) and water (8 ml) were added to4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g), while cooling. Thenthe reaction mixture was stirred for 5 days at room temperature. Afterevaporation in vacuo, the residue was triturated with 4N hydrochloricacid, after which the resulting4-isopropylamino-3-nitro-5-sulphamyl-benzoic acid was collected bysuction. After recrystallization from aqueous ethanol, the acid wasobtained with a melting point of 206°C (decomp.).

B. 3-amino-4-isopropylamino-5 -sulphamyl-benzoic acid

By substituting 4-isopropylamino-3-nitro-5-sulphamyl-benzoic acid forthe 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the abovecompound was obtained with a melting point of 226°C (decomp.).

EXAMPLE 26 3-Amino-4-(N-methyl-ethanolamino)-5-sulphamyl-benzoic acid

A. 4-(n-methyl-ethanolamino)-3-nitro-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (14 g),2-methylamino-ethanol (19 g), and 50% ethanol (30 ml) in water wasstirred at 50°C for 2 hours. After addition of water (100 ml), 1Nhydrochloric acid was added until pH 2, causing precipitation of4-(N-methyl-ethanolamino)-3-nitro-5-sulphamyl-benzoic acid. Afterrecrystallization from water, the melting point was 125°-127°C.

B. 3-amino-4-(N-methyl-ethanolamino)-5-sulphamyl-benzoic acid

4-(N-Methyl-ethanolamino)-3-nitro-5-sulphamyl-benzoic acid (9 g) wasdissolved in water by adjusting the pH to 8 by means of 1N sodiumhydroxide. Raney-Nickel catalyst (1 g) was added, and the solution washydrogenated until the hydrogen uptake had become negligible. Thecatalyst was removed by filtration, and the resulting3-amino-4-(N-methyl-ethanolamino)-5-sulphamyl-benzoic acid wasprecipitated from the filtrate by addition of 4N hydrochloric acid untilpH 2.5. After recrystallization from water, the melting point was209°-211°C.

EXAMPLE 27 3-Amino-4-piperidino-5-sulphamyl-benzoic acid

A. 3-nitro-4-piperidino-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (2.8 g),piperidine (3.4 g), and water (13 ml) was stirred at 95°C for 2 hours.Then the reaction mixture was adjusted to a pH of 2.5 by the addition of4N hydrochloric acid, and the precipitated3-nitro-4-piperidino-5-sulphamyl-benzoic acid was collected andrecrystallized from aqueous methanol. The melting point was 237°-238°C(decomp.).

B. 3-amino-4-piperidino-5-sulphamyl-benzoic acid

By substituting 3-nitro-4-piperidino-5-sulphamyl-benzoic acid for the4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the abovecompound was obtained with a melting point of 279°C (decomp.) afterrecrystallization from aqueous methanol.

EXAMPLE 28 3-Amino-4-morpholino-5-sulphamyl-benzoic acid

A. 4-morpholino-3-nitro-5-sulphamyl-benzoic acid

By substituting morpholine (3.48 g) for piperidine in Example 27 A, theabove compound was obtained with a melting point of 273°C (decomp.).

B. 3-amine-4-morpholino-5-sulphamyl-benzoic acid

By substituting 4-morpholino-3-nitro-5-sulphamyl-benzoic acid for the4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the abovecompound was obtained with a melting point of 297°C (decomp.) afterrecrystallization from aqueous methanol.

EXAMPLE 29 3-Amino-4-(3-dimethylaminopropylamino)-5-sulphamyl-benzoicacid

A. 4-(3-dimethylaminopropylamino)-3-nitro-5-sulphamyl-benzoic acid

To a suspension of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g) inwater (24 ml), 3-dimethylaminopropylamine (120 ml) was added, whilecooling. Then the reaction mixture was heated to 100°C and kept at thistemperature for 2 hours. After cooling and evaporating in vacuo todryness, the residue was dissolved in water (80 ml) and adjusted to a pHof 7.5 by addition of 4N hydrochloric acid. The precipitated4-(3-dimethylaminopropylamino)-3-nitro-5-sulphamyl-benzoic acid wascollected by suction and recrystallized from water. The melting pointwas 262°C (decomp.).

B. 3-amino-4-(3-dimethylaminopropylamino)-5-sulphamyl-benzoic acid

4-(3-Dimethylaminopropylamino)-3-nitro-5-sulphamyl-benzoic acid (6.92 g)was dissolved in 2N sodium hydroxide (25 ml), and the solution washydrogenated at room temperature and 1.1 atmospheres hydrogen pressureafter the addition of a palladium-on-carbon catalyst (0.35 g catalystcontaining 10% Pd.). After the hydrogen uptake had become negligible,the catalyst was removed by filtration, and the filtrate was adjusted toa pH of 8 by addition of 4N hydrochloric acid. The precipitated3-amino-4-(3-dimethylaminopropylamino)-5-sulphamyl-benzoic acid wascollected by suction and recrystallized from water. After drying invacuo at 115°C for 2 hours, the melting point was 264°C (decomp.).

EXAMPLE 30 3-Amino-4-(β-naphthylamino)-5-sulphamyl-benzoic acid

A. 4-(β-naphthylamino)-3-nitro-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g),β-naphthylamine (43.2 g), dry ethanol (250 ml), and dry sodium acetate(8.2 g) was refluxed for 5 hours. Then the reaction mixture wasevaporated in vacuo, and the residue was triturated with warm 1Nhydrochloric acid (350 ml). The precipitated4-(β-naphthylamino-3-nitro-5-sulphamyl-benzoic acid was filtered off andrecrystallized from aqueous ethanol. The compound was obtained as amonohydrate and had a melting point of 262°C (decomp.).

B. 3-amino-4-(β-naphthylamino)-5-sulphamyl-benzoic acid

By substituting 4-(β-naphthylamino)-3-nitro-5-sulphamyl-benzoic acid forthe 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the abovecompound was obtained with a melting point of 245°C.

EXAMPLE 31 3-Amino-4-phenylthio-5-sulphamyl-benzoic acid

A. 3-nitro-4-phenylthio-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g),thiophenol (10.25 ml), and 1N sodium bicarbonate (300 ml) was refluxedfor 3 hours. After cooling, the precipitated sodium salt of3-nitro-4-phenylthio-5-sulphamyl-benzoic acid was filtered off. Thesodium salt was dissolved in hot water (200 ml), and3-nitro-4-phenylthio-5-sulphamyl-benzoic acid was precipitated by theaddition of 4N hydrochloric acid until the pH was 1. After isolation andrecrystallization from aqueous ethanol, the acid was obtained with amelting point of 245°-247°C.

B. 3-amino-4-phenylthio-5-sulphamyl-benzoic acid

A mixture of ammonium chloride (2.4 g), metallic iron powder (24 g),concentrated hydrochloric acid (0.1 ml), and water (60 ml) was heated to90°C with stirring, and 3-nitro-4-phenylthio-5-sulphamyl-benzoic acid(10 g) was added in small portions during 2 hours. The reaction mixturewas stirred on a steam bath for an additional 2 hours. After theaddition of dilute sodium hydroxide until the pH was 8, the hot reactionmixture was filtered, and the filter-cake was washed with warm dilutesodium hydroxide. After the addition of 4N hydrochloric acid to thefiltrate until its pH was 2 and cooling, the resulting precipitate,consisting of 3-amino-4-phenylthio-5-sulphamyl-benzoic acid, wasfiltered off and dried at 78°C in vacuo. The melting point was 285°C.

EXAMPLE 32 3-Amino-4-n-butylthio-5-sulphamyl-benzoic acid

A. 4-n-Butylthio-3-nitro-5-sulphamyl-benzoic acid and sodium salt

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g),butylmercaptan (11 ml), and 1N sodium bicarbonate (300 ml) was stirredat 90°C for 22 hours. After cooling, the precipitated sodium salt of4-n-butylthio-3-nitro-5-sulphamyl-benzoic acid was filtered off. Thesalt was dissolved in hot water, and the acid was precipitated byaddition of 4N hydrochloric acid. After cooling, the acid was isolatedand recrystallized from aqueous ethanol. The melting point was173°-174°C.

B. 3-amino-4-butylthio-5-sulphamyl-benzoic acid

To a solution of sodium dithionite (15.9 g) in aqueous ammonia (13 g NH₃in 150 ml water) 4-n-butylthio-3-nitro-5-benzoic acid (8.35 g) was addedin portions during 1 hour, while stirring. The reaction mixture was thenheated on a steam bath for 30 minutes. Hydrochloric acid was added untilthe pH was 1, and heating was continued for 1 hour. After cooling, thepH was adjusted to 3 by the addition of 2N sodium hydroxide, andisopropanol (25 ml) was added. The precipitated3-amino-4-n-butylthio-5-sulphamyl-benzoic acid was filtered off andrecrystallized from aqueous ehtanol. The melting point was 223°-224°C.

EXAMPLE 33 3-Amino-5-sulphamyl-4-(o-tolylthio)-benzoic acid

A. 3-nitro-5-sulphamyl-4-(o-tolylthio)-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g),o-thiocresol (12.4 g), and 1N sodium bicarbonate (300 ml) was refluxedfor 3 hours. After cooling, the precipitated sodium salt of3-nitro-5-sulphamyl-4-o-tolylthio-benzoic acid was filtered off andwashed with 1N sodium bicarbonate solution. The sodium salt wasdissolved in hot water (250 ml), and the acid was precipitated by theaddition of 4N hydrochloric acid (17 ml). After isolation,recrystallization from aqueous ethanol, and drying at 115°C and 10 mm Hgfor 3 hours, the acid was obtained with a melting point of 165°-166°C.

B. 3-amino-5-sulphamyl-4-(o-tolylthio)-benzoic acid

By substituting 3-nitro-5-sulphamyl-4-(o-tolylthio)-benzoic acid (7.7 g)for the 4-butylthio-3-nitro-5-sulphamyl-benzoic acid of Example 32 B,3-amino-5-sulphamyl-4-(o-tolylthio)-benzoic acid was obtained with amelting point of 277°C.

EXAMPLE 34 3-Amino-4-phenylsulphonyl-5-sulphamyl-benzoic acid

A. 3-nitro-4-phenylsylphonyl-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (24 g),benzenesulphinic acid (13 g), sodium acetate (16 g), and anhydrousethanol (65 ml) was stirred at 78°C for 20 hours. After cooling, theprecipitated sodium salt of3-nitro-4-phenylsulphonyl-5-sulphamyl-benzoic acid was collected bysuction. The sodium salt was dissolved in aqueous ethanol, and the acidwas precipitated by acidification with 4N hydrochloric acid. Aftercollection by suction and recrystallization from aqueous ethanol, the3-nitro-4-phenylsulphonyl-5-sulphamyl-benzoic acid had a melting pointof 291°C (decomp.).

B. 3-amino-4-phenylsulphonyl-5-sulphamyl-benzoic acid

A suspension of 3-nitro-4-phenylsulphonyl-5-sulphamyl-benzoic acid (6 g)in water (300 ml) was hydrogenated at room temperature and 1.1atmospheres hydrogen pressure after addition of Pd-on-carbon catalyst(0.3 g catalyst containing 10% Pd). After the hydrogen uptake had becomenegligible, the reaction mixture was neutralized by addition of 2Nsodium hydroxde, and the catalyst was removed from the resultingsuspension by filtration. The filtrate was adjusted to a pH of 2.5 byaddition of 4N hydrochloric acid, and the precipitated3-amino-4-phenylsulphonyl-5-sulphamyl-benzoic acid was collected bysuction. After recrystallization from aqueous ethanol, the acid had amelting point of 278°C (decomp.).

EXAMPLE 35 3-Amino-4-n-butylsulphinyl-5-sulphamyl-benzoic acid

A. 4-n-Butylsulphinyl-3-nitro-5-sulphamyl-benzoic acid

To a solution of 4-n-butylthio-3-nitro-5-sulphamyl-benzoic acid (10 g)in acetic acid (150 ml), perhydrol (30 ml of 30% hydrogen peroxide inwater) was added, while stirring. After additional stirring for 24 hoursat room temperature, the reaction mixture was diluted with water (150ml) and left standing for 8 hours. The precipitated4-n-butylsulphinyl-3-nitro-5-sulphamyl-benzoic acid was collected bysuction, recrystallized from aqueous ethanol, and dried in vacuo. Theacid was obtained as a semi-hydrate with a melting point of 165°C(decomp.).

B. 3-amino-4-n-butylsulphinyl-5-sulphamyl-benzoic acid

To a solution of sodium dithionite (7.3 g) in water (50 ml) conc.aqueous ammonia (25 ml) was added, after which4-n-butylsulphinyl-3-nitro-5-sulphamyl-benzoic acid (4 g) was added inportions at 25°C, while stirring. The reaction mixture was heated on asteam bath for 30 minutes. Then 4N hydrochloric acid was added until apH of 1, while the heating was continued. After the evolution of sulphurdioxide had ceased, the reaction mixture was adjusted to a pH of 2.5 byaddition of 2N sodium hydroxide, and cooled. The precipitated3-amino-4-n-butylsulphinyl-5-sulphamyl-benzoic acid was collected bysuction, recrystallized from aqueous ethanol, and dried in vacuo at115°C. The acid was obtained with a melting point of 237°C (decomp.).

EXAMPLE 36 3-Amino-5-sulphamyl-4-(β, β, β-trifluoroethoxy)-benzoic acid

A. 3-nitro-5-sulphamyl-4-(β, β, β-trifluoroethoxy)-benzoic acid

To a solution of sodium β, β, β -trifluoroethoxide in β, β,β-trifluoroethanol (prepared by dissolving 2.1 g of sodium in 45 ml of β,β ,β-trifluoroethanol), 4-chloro-3-nitro-5-sulphamyl-benzoic acid (4.2g) was added, and the resulting solution was refluxed for 5 days. Afterevaporation of the reaction mixture in vacuo, water (50 ml) was added,and the aqueous solution was acidified with 4N hydrochloric acid. Afterstanding in a refrigerator, the precipitate was collected by suction.After several recrystallizations from aqueous ethanol, the3-nitro-5-sulphamyl-4-(β ,β ,β-trifluoroethoxy)-benzoic acid wasobtained with a melting point of 195°-197°C.

B. 3-amino-5-sulphamyl-4-(β ,β ,β-trifluoroethoxy)-benzoic acid

3-Nitro-5-sulphamyl-4-(β,β,β-trifluoroethoxy)-benzoic acid (2 g) inwater (30 ml) was adjusted to a pH of 9 by addition of lithiumhydroxide, and the resulting solution was hydrogenated at roomtemperature and at a hydrogen pressure of 1.1 atmospheres after additionof Pd-on-carbon catalyst (0.2 g catalyst containing 10% Pd). After thehydrogen uptake had become negligible, the catalyst was removed byfiltration, and the 3-amino-5-sulphamyl-4-(β ,β,β-trifluoroethoxy)-benzoic acid was precipitated from the filtrate byaddition of 4N hydrochloric acid until a pH of 2.5. Afterrecrystallization from aqueous ethanol and drying, the melting point ofthe compound was 253°-254°C.

EXAMPLE 37 3-Amino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid

A. ethyl-4-chloro-3-nitro-5-sulphamyl-benzoate

A solution of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g) in dryethanol (250 ml) was saturated with gaseous hydrogen chloride. Thereaction mixture was allowed to ware during the inlet of the hydrogenchloride. After standing for 3 hours, the solvent was removed byevaporation in vacuo. The residue was dissolved in a mixture of diethylether and dilute sodium hydrogen carbonate. The organic layer wasseparated, washed with water and dried. The diethyl ether was distilledoff, and the residue was recrystallized from dry ethanol, yielding theethyl-4-chloro-3-nitro-5-sulphamyl-benzoate with a melting point of154°C.

B. ethyl-4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoate

A mixture of ethyl-4-chloro-3-nitro-5-sulphamyl-benzoate (3.08 g) and6-amino-2-methyl-pyridine (3.24 g) was melted on an oil bath at 140°Cand kept at this temperature for 2 hours, while stirring. The still warmreaction mixture was triturated with ethanol (35 ml) and after cooling,the ethyl-4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoate wascollected by suction and washed with ethanol. After recrystallizationfrom acetonitrile, the compound had a melting point of 203°-204°C.

C. 4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoic acid

Ethyl-4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoate (2 g) wasdissolved in 1N sodium hydroxide (30 ml) and heated on a steam bath for1 hour. After cooling, water (50 ml) was added, and the pH of thereaction mixture was adjusted to 4.5 by addition of 1N hydrochloricacid. The precipitated4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoic acid wascollected by suction, washed with water, and dried. The compound had amelting point of 305°C (decomp.).

D. 3-amino-4-(4-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid

A suspension of 4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid (4g) in water (20 ml) was adjusted to pH 8 by addition of 1N lithiumhydroxide, and the resulting solution was hydrogenated at roomtemperature and at a hydrogen pressure of 1.1. atmospheres afteraddition of a Pd-on-carbon catalyst (2.0 g catalyst containing 10% Pd).After the hydrogen uptake had become negligible, the catalyst wasremoved by filtration, and the3-amino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid wasprecipitated from the filtrate by addition of 4N hydrochloric acid untila pH of 5. After recrystallization from aqueous ethanol and drying invacuo, the melting point of the compound was 256°C (decomp.).

EXAMPLE 38 3-Amino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid

A. n-Butyl-4-chloro-3-nitro-5-sulphamyl-benzoate

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (10 g), n-butanol(100 ml), and conc. sulphuric acid (2 ml) was refluxed for 4 hours,during which 50 ml of the solvent were distilled off slowly. Aftercooling, the n-butyl-4-chloro-3-nitro-5-sulphamyl-benzoate was isolatedby filtration and recrystallized from n-butanol. The compound wasobtained with a melting point of 140°-141°C.

B. n-Butyl-4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoate

To a solution of sodium n-butoxide in n-butanol (prepared from 0.074 gof sodium and 16 ml of dry n-butanol), 4-benzyloxyphenol (0.64 g), andn-butyl-4-chloro-3-nitro-5-sulphamyl-benzoate were added. The reactionmixture was refluxed for 4 hours and cooled, whereafter the precipitatedn-butyl-4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoate was isolatedand recrystallized from n-butanol. After drying, the compound wasobtained with a melting point of 138°-144°C.

C. 4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid

A solution ofn-butyl-4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoate (7.3 g) in1N sodium hydroxide (120 ml) was heated on a steam bath for 45 minutes.After cooling and acidification by addition of 4N hydrochloric acid, theprecipitated 4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid wasisolated by filtration and recrystallized from aqueous ethanol. Afterdrying, the compound was obtained with a melting point of 247°C.

D. 3-amino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid

A suspension of 4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid(10 g) in water (250 ml) was adjusted to pH 11 by addition of 1N sodiumhydroxide. The resulting solution was hydrogenated at room termperatureand at 1.1 atmospheres hydrogen pressure after addition of a platinumoxide catalyst (0.4 g). After the hydrogen uptake had become negligible,the catalyst was removed by filtration, and the3-amino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid was precipitatedby adjusting the filtrate to pH 2.5 by addition of 4N hydrochloric acid.After recrystallization from aqueous ethanol and drying, the compoundwas obtained with a melting point of 264°-265°C.

EXAMPLE 39 3-Amino-4-phenoxy-5-sulphamyl-benzoic acid

A. 3-nitro-4-phenoxy-5-sulphamyl-benzoyl chloride

A mixture of 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid (5g) and thionylchloride (50 ml) was heated on a steam bath for 5 hours. Afterevaporation in vacuo to dryness, the compound was obtained as a crudeproduct, which was used in the next step without further purification.

B. 3-nitro-4-phenoxy-5-sulphamyl-benzamide

3-Nitro-4-phenoxy-5-sulphamyl-benzoyl chloride (4 g) was added inportions to liquid ammonia (40 ml). Then excess of ammonia was distilledoff, and the residue was triturated with water (50 ml). The precipitated3-nitro-4-phenoxy-5-sulphamyl-benzamide was isolated by filtration andrecrystallized twice from aqueous ethanol. After drying in vacuo, thecompound was obtained with a melting point of 255°-256°C.

C. 3-amino-4-phenoxy-5-sulphamyl-benzamide

To a suspension of 3-nitro-4-phenoxy-5-sulphamyl-benzamide (2.4 g) inwater (25 ml) 1N lithium hydroxide (10 ml) was added. The resultingsolution was hydrogenated at room temperature and at 1.1 atmosphereshydrogen pressure after addition of Pd-on-carbon catalyst (0.2 gcatalyst containing 10% Pd). After the hydrogen uptake had becomenegligible, the catalyst was removed by filtration, and the filtrate wasthen adjusted to pH 7.5 by addition of 4N hydrochloric acid. Theprecipitated 3-amino-4-phenoxy-5-sulphamyl-benzamide was isolated anddried in vacuo. The compound was obtained with a melting point of291°-292°C.

d. 3-amino-4-phenoxy-5-sulphamyl-benzoic acid

A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzamide (1 g) and 1N sodiumhydroxide (20 ml) was refluxed for 1 hour. After cooling, the3-amino-4-phenoxy-5-sulphamyl-benzoic acid was precipitated from thereaction mixture by addition of 4N hydrochloric acid until pH 2.5. Afterseveral recrystallizations from aqueous ethanol and drying, the compoundwas obtained with a melting point of 252°-253°C.

EXAMPLE 40 3-Amino-5-acetylsulphamyl-4-phenoxy-benzoic acid

A. 5-acetylsulphamyl-3-nitro-4-phenoxy-benzoic acid

3-Nitro-4-phenoxy-5-sulphamyl-benzoic acid (10 g) was dissolved in water(250 ml) by adjusting the pH to 8 by addition of 1N lithium hydroxide.Then acetic anhydride (12 g) was added dropwise, while stirring andkeeping the pH constant at pH 9 by means of 1N lithium hydroxide, usingan automatic titrator. After the acetic anhydride was consumed, thereaction mixture was acidified by addition of 4N hydrochloric acid. Theprecipitated 5-acetylsulphamyl-3-nitro-4-phenoxy-benzoic acid wasisolated by filtration and recrystallized from aqueous ethanol. Thecompound was obtained with a melting point of 270°-271°C.

B. 3-amino-5-acetylsulphamyl-4-phenoxy-benzoic acid

By substituting 5-acetylsulphamyl-3-nitro-4-phenoxy-benzoic acid for the3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B, the abovecompound was obtained as a monohydrate with a melting point of290°-293°C.

EXAMPLE 41 3-n-Butylamino-4-phenoxy-5-sulphamyl-benzoic acid and itssodium salt

To a suspension of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (10 g) inn-butanol (200 ml) concentrated sulphuric acid (2 ml) was added, whilestirring. The reaction mixture was heated under reflux at suchconditions that the water formed during the reaction was separated. Whenthe NMR-spectrum of a sample of the reaction mixture diluted withn-butanol showed at the two doublets of the aromatic protons of the ringcarrying the sulphamyl group that more than 90% of the formedbutyl-3-amino-4-phenoxy-5-sulphamyl-benzoate intermediate was convertedinto the corresponding 3-n-butylamino-benzoate, which caused a frequenceshift to a higher field, 2N sodium hydroxide (200 ml) was added, and theboiling was continued for 45 minutes. After this saponification, thereaction mixture was neutralized to a pH of 8 by the addition ofconcentrated hydrochloric acid. After cooling, the sodium saltprecipitated. It was filtered off and recrystallized from water (100ml). The sodium salt, which crystallized with 3 molecules of water ofcrystallization, was then dissolved in boiling water (200 ml). 1NHydrochloric acid was added until the pH was 2.5, and, after cooling,the precipitated 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid wascollected by filtration. After recrystallization from aqueous ethanoland drying, the pure compound was obtained with a melting point of230°-231°C.

EXAMPLE 42 Ethanolamine salt of3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid

3-n-Butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1.82 g) was dissolvedin boiling ethanol (20 ml) and a solution of ethanolamine (0.3 g) inethanol (15 ml) was added. After cooling, the precipitated ethanolaminesalt was collected by filtration and recrystallized from ethanol. Themelting point was 194°-195°C.

EXAMPLE 43 Potassium salt of3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid

The ethanolamine salt of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoicacid (10 g) was dissolved in boiling water (50 ml), and aqueoussaturated potassium chloride (5 ml) was added. After cooling, theprecipitated potassium salt was collected by filtration andrecrystallized from water. The salt was obtained as a hydrate.

EXAMPLE 44 Neutral calcium salt of3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid

The ethanolamine salt of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoicacid (4.25 g) was dissolved in water (150 ml), and an aqueous solutionof calcium chloride (2 ml containing 40% CaCl₂) was added, whilestirring. The precipitated calcium salt was collected by suction anddried. The salt contained 3.5 molecules of water of crystallization.

EXAMPLE 45 Methyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate

A mixture of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (3 g) andmethanol (60 ml) was saturated with gaseous hydrogen chloride. Thereaction mixture was allowed to warm during the saturation. Aftercooling and standing for 5 hours, the reaction mixture was evaporated invacuo, and the residue was recrystallized from methanol (12 ml), wherebythe methyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate was obtainedwith a melting point of 148°C.

EXAMPLE 46 Cyanomethyl-3n-butylamino-4-phenoxy-5-sulphamyl-benzoate

A mixture of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g),chloroacetonitrile (0.625 g), triethylamine (0.28 g), and dry acetone(10 ml) was refluxed for 19 hours. After cooling, the precipitatedtriethylamine hydrochloride was removed by filtration, and the filtratewas evaporated in vacuo. To the residue, water (20 ml) and ethylacetate(50 ml) were added, and the pH of the aqueous layer was adjusted to pH7.5. The organic layer was then separated, washed with dilute sosiumhydrogen carbonate, dried, and evaporated in vacuo. The residue wasrecrystallized several times from chloroform/petroleum ether. Therebythe cyanomethyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate wasobtained with a melting point of 159°-161°C.

EXAMPLE 47 3-Butylamino-4-(4-sulphamylphenxoy)-5-sulphamyl-benzoic acid

To chlorosulphonic acid (5 ml),3-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g) was added inportions, while stirring and keeping the temperature below 45°C. Thereaction mixture was stirred to 10 minutes and then poured into icewater (10 g of ice and 20 ml of water). The precipitated3-butylamino-4-(4-chlorosulphonylphenoxy)-5-sulphamyl-benzoic acid wasisolated by filtration and without further purification added to aqueousammonia (10 ml containing 2.5 g of ammonia). Excess of ammonia wasremoved by evaporation, and the resulting solution was adjusted to pH2.5 by addition of 4N hydrochloric acid. The precipitated3-butylamino-4-(4-sulphamylphenoxy)-5-sulphamyl-benzoic acid wasisolated by filtration, recrystallized from aqueous ethanol, and dried.The obtained compound had a melting point of 265°C.

EXAMPLE 48 3-n-Butylmethylamino-4-phenoxy-5-sulphamyl-benzoic acid

A suspension of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g)in aqueous ethanol (20 ml of ethanol and 20 ml of water) containingformaldehyde (0.35 g) was hydrogenated at room temperature and at 1.1atmospheres hydrogen pressure after addition of Pd-on-carbon powder (0.1g catalyst containing 10% of Pd). When the hydrogen uptake had becomenegligible, the reaction mixture was warmed to 60°C, and the catalystwas filtered off. After addition of water (15 ml) to the filtrate andcooling, the precipitated3-n-butylmethylamino-4-phenoxy-5-sulphamyl-benzoic acid was collected byfiltration and recrystallized from aqueous ethanol. After drying invacuo at 115°C, the compound was obtained with a melting point of159°-162°C.

EXAMPLE 49 3-n-Butylamino-4-phenoxy-5-sulphamyl-benzamide

To a solution of 3-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g)in dry acetone (10 ml), triethylamine (0.278 g) was added.Methanesulphonyl chloride (0.315 g) in dry acetone (5 ml) was added tothe reaction mixture, while stirring. The agitation was continued for1.5 hours at 20°C. The resulting solution of the mixed anhydride wasadded dropwise to aqueous ammonia (30 ml containing 7 g of ammonia),while stirring. The excess of ammonia and acetone were removed byevaporation under reduced pressure. The pH of the reaction mixture wasadjusted to 7.5 by means of 4N hydrochloric acid, and the precipitated3-butylamino-4-phenoxy-5-sulphamyl-benzamide was isolated by filtrationand recrystallized several times from aqueous ethanol. After drying invacuo at 115°C, the compound was obtained with a melting point of223°-224°C.

EXAMPLE 50 3-Benzylamino-4-phenylthio-5-sulphamyl-benzoic acid

A suspension of 3-amino-4-phenylthio-5-sulphamyl-benzoic acid (4.05 g)in water (100 ml) was adjusted to pH 7.5 by addition of 1N lithiumhydroxide. Benzyl bromide (2.2 g) was added and, under stirring, the pHwas kept at 7.5 by automatic titration with lithium hydroxide. After thebase comsumption had become negligible, the pH was adjusted to 2.5 byaddition of dilute hydrochloric acid. The precipitated3-benzylamino-4-phenylthio-5-sulphamyl-benzoic acid was collected andrecrystallized from ethanol, whereafter the compound was obtained with amelting point of 224°-225°C.

3-Benzylamino-4-phenoxy-5-sulphamyl-benzoic acid

By substituting 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (3.8 g) forthe 3-amino-4-phenylthio-5-sulphamyl-benzoic acid above,3-benzylamino-4-phenoxy-5-sulphamyl-benzoic acid was obtained, afterrecrystallization from dilute ethanol, with a melting point of264°-265°C.

EXAMPLE 51 3-n-Butylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid

A. 3-n-Butylamino-4-phenylthio-5-sulphamyl-benzoic acid and its sodiumsalt

To a suspension of 3-amino-4-phenylthio-5-sulphamyl-benzoic acid (10 g)in n-butanol (200 ml), concentrated sulphuric acid (2 ml) was addedwhile stirring. The reaction mixture was heated under reflux underconditions at which the water formed during the reaction was separated.When the NMR-spectrum of a sample of the reaction mixture diluted withn-butanol, showed at the two doublets of the aromatic protons of thering carrying the sulphamyl group that more than 90 percent of theformed butyl-3-amino-4-phenylthio-5-sulphamyl-benzoate intermediate wasconverted into the corresponding 3-n-butylaminobenzoate, which caused afrequence shift to a higher field, 2N sodium hydroxide (200 ml) wasadded, and the boiling was continued for 45 minutes. After thissaponification, the reaction mixture was neutralized to a pH of 8 by theaddition of concentrated hydrochloric acid. After cooling, the sodiumsalt of 3-n-butylamino-4-phenylthio-5-sulphamyl-benzoic acidprecipitated. It was filtered off and recrystallized from water (100ml). The sodium salt, which crystallized with 3 molecules of water ofcrystallization, was then dissolved in boiling water (200 ml). 1Nhydrochloric acid was added until the pH was 2.5, and, after cooling,the precipitated 3-n-butylamino-4-phenylthio-5-sulphamyl-benzoic acidwas collected by filtration. After recrystallization from aqueousethanol and drying, the pure compound was obtained with a melting pointof 203°-204°C.

B. 3-n-Butylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid

To a suspension of 3-n-butylamino-4-phenylthio-5-sulphamyl-benzoic acid(0.5 g) in acetic acid (5 ml), perhydrol (2.5 ml of 30% hydrogenperoxide in water) was added while stirring. The reaction mixture wasstirred for an additional 24 hours at 30°C, after which the3-n-butylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid was collectedby suction and washed with aqueous acetic acid. After recrystallizationfrom aqueous ethanol, the compound was obtained with a melting point of203°-204°C (decomp.).

EXAMPLE 52 4-Anilino-3-benzylamino-5-sulphamyl-benzoic acid

A. ethyl-4-anilino-3-benzylamino-5-sulphamyl-benzoate

A mixture of 3-amino-4-anilino-5-sulphamyl-benzoic acid (2 g), benzylbromide (3 g), and ethanol (50 ml 99.9%) was refluxed for 8 hours. Aftercooling, the ethyl-4-anilino-3-benzylamino-5-sulphamyl-benzoatecrystallized and was collected by suction. After recrystallization fromethanol the melting point was 160°-161°C.

B. 4-anilino-3-benzylamino-5-sulphamyl-benzoic acid

A solution of ethyl-4-anilino-3-benzylamino-5-sulphamyl-benzoate (1 g)in 1N sodium hydroxide (15 ml) was heated on a steam bath for 1 hour.After cooling, the 4-anilino-3-benzylamino-5-sulphamyl-benzoic acid wasprecipitated by addition of acetic acid, collected and recrystallizedfrom 6% ethanol in water. The melting point was 248°-249°C.

EXAMPLE 53 4-Anilino-3-benzylamino-5-phenylsulphamyl-benzoic acid

A. ethyl-4-anilino-3-benzylamino-5-phenylsulphamyl-benzoate.

By replacing, in Example 52 A, 3-amino-4-anilino-5-sulphamyl-benzoicacid (2 g) by 3-amino-4-anilino-5-phenylsulphamyl-benzoic acid (4.4 g)and increasing the amount of benzyl bromide to 3.9 g,ethyl-4-anilino-3-benzylamino-5-phenylsulphamyl-benzoate was obtainedwith a melting point of 166°-167°C.

B. 4-anilino-3-benzylamino-5-phenylsulphamyl-benzoic acid

A solution of ethyl-4-anilino-3-benzylamino-5-phenylsulphamyl-benzoate(3 g) in 1N sodium hydroxide (30 ml) was heated on a steam bath for 1hour. The 4-anilino-3-benzylamino-5-phenylsulphamyl-benzoic acid wasprecipitated by addition of 4N hydrochloric acid until pH 2, andrecrystallized from acetone-water and 80% ethanol in water; the meltingpoint was 243°C.

EXAMPLE 54 3-Benzylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid

To a suspension of 3-benzylamino-4-phenylthio-5-sulphamyl-benzoic acid(0.8 g) in acetic acid (20 ml), perhydrol (1.5 ml of 30% hydrogenperoxide in water) was added while stirring. The reaction mixture wasstirred for an additional 75 hours at room temperature, after which the3-benzylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid was collectedby filtration and washed with acetic acid. After recrystallization fromaqueous methanol and drying, the acid had a melting point of 234°C.

EXAMPLE 55 3-Benzylamino-4-n-butylsulphinyl-5-sulphamyl-benzoic acid

A mixture of 3-amino-4-n-butylsulphinyl-5-sulphamyl-benzoic acid (2 g),benzyl bromide (3.5 g), and dry ethanol (20 ml) was refluxed for 16hours. The reaction mixture was evaporated in vacuo. The residue,containing theethyl-3-benzylamino-4-n-butylsulphinyl-5-sulphamyl-benzoate, wassaponified by addition of 1N sodium hydroxide (30 ml) and standing for16 hours at room temperature. After extraction with diethyl ether, theaqueous layer was adjusted to a pH of 7.4 by addition of 4N hydrochloricacid and the sodium salt of3-benzylamino-4-n-butylsulphinyl-5-sulphamyl-benzoic acid wasprecipitated by addition of sodium chloride (5 g). The sodium salt wasisolated and recrystallized from a little amount of water. The salt wasdissolved in aqueous ethanol (25% ethanol in water) and the3-benzylamino-4-n-butylsulphinyl-5-sulphamyl-benzoic acid wasprecipitated by addition of 4N hydrochloric acid until a pH of 3. Afterrecrystallization from aquous ethanol and drying in vacuo, the compoundwas obtained as a monohydrate with a melting point of 182°C (decomp.).

EXAMPLE 563-(3,4-Methylenedioxybenzylamino)-4-phenoxy-5-sulphamyl-benzoic acid

To a suspension of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (1.54 g)in acetic acid (30 ml), piperonal (0.75 g) was added. After the additionof platinum oxide (25 mg) and a catalytic amount of p-toluenesulphonicacid, the reaction mixture was hydrogenated at room temperature and 1.1atmospheres hydrogen pressure until the hydrogen uptake had becomenegligible. Then the reaction mixture was filtered by suction. Thefilter cake was suspended in water (100 ml), and the pH was adjusted to8.5 by addition of lithium hydroxide. After the catalyst had beenremoved from the resulting solution, the3-(3,4-methylenedioxybenzylamino)-4-phenoxy-5-sulphamyl-benzoic acid wasprecipitated from the filtrate by addition of 4N hydrochloric acid untilthe pH was 3. After recrystallization from methanol, the melting pointwas 229°-230°C.

3-(Methoxy-, methyl-, orchloro-benzylamino)-4-phenoxy-5-sulphamyl-benzoic acids

By substituting methyl-, methoxy-, or chloro-benzaldehyde (0.005 mole)for the piperonal above and recrystallization from aqueous ethanol, thecorresponding benzoic acids were obtained.

EXAMPLE 57 3-n-Hexylamino-4-phenoxy-5-sulphamyl-benzoic acid, and itssodium salt

A. n-Hexyl-3-n-hexylamino-4-phenoxy-5-sulphamyl-benzoate

A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (4.62 g),1-bromo-n-hexane (5 g), methanesulphonic acid (0.05 ml), and n-hexanol(40 ml) was refluxed for 60 hours. After cooling, the precipitatedn-hexyl-3-n-hexylamino-4-phenoxy-5-sulphamyl-benzoate was collected andrecrystallized from hexanol. The melting point was 137°-138°C.

B. 3-n-Hexylamino-4-phenoxy-5-sylphamyl-benzoic acid, and its sodiumsalt

n-Hexyl-3-n-hexylamino-4-phenoxy-5-sulphamyl-benzoate (2 g) wasdissolved in 1N sodium hydroxide (30 ml) and heated on a steam bath for1 hour. Then the reaction mixture was adjusted to a pH of 8 by additionof 4N hydrochloric acid. After cooling, the sodium salt of3-n-hexylamino-4-phenoxy-5-sulphamyl-benzoic acid was collected bysuction and dried. The sodium salt was dissolved in hot water (100 ml),and the acid was precipitated by the addition of 4N hydrochloric aciduntil the pH was 2.5. After cooling, the acid was collected andrecrystallized from aqueous ethanol. The melting point was 221°-223°C.

EXAMPLE 58 3-Allylamino-4-phenoxy-5-sulphamyl-benzoic acid

A. ethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate

A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (3.08 g), allylbromide (7.25 g), and dry ethanol was refluxed for 24 hours. Aftercooling, the precipitatedethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate was filtered off andrecrystallized from ethanol. The melting point of the ester was153°-154°C.

B. 3-allylamino-4-phenoxy-5-sulphamyl-benzoic acid

Ethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate (1 g) was dissolved in1N sodium hydroxide (15 ml) and left standing at room temperature for 24hours. Then water (5 ml) was added, and the pH was adjusted to 3 by theaddition of 4N hydrochloric acid. The precipitated3-allylamino-4-phenoxy-5-sulphamyl-benzoic acid was collected and dried.The melting point was 223°-225°C.

EXAMPLE 59 4-Phenoxy-3-propargylamino-5-sulphamyl-benzoic acid

A. ethyl-4-phenoxy-3-propargylamino-5-sulphamyl-benzoate

By substituting propargyl bromide (4.8 g) for the allyl bromide ofExample 58 A and extending the reaction time to 48 hours,ethyl-4-phenoxy-3-propargylamino-5-sulphamyl-benzoate was obtained witha melting point of 189°-190°C.

B. 4-phenoxy-3-proparglyamino-5-sulphamyl-benzoic acid

By substituting ethyl-4-phenoxy-3-propargylamino-5-sulphamyl-benzoatefor the ethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate of Example 58B and by recrystallizing from dilute ethanol,4-phenoxy-3-propargylamino-5-sulphamyl-benzoic acid was obtained with amelting point of 222°-223°C.

EXAMPLE 60 4-Phenoxy-3-n-propylamino-5-sulphamyl-benzoic acid

A. ethyl-4-phenoxy-3-n-propylamino-5-sulphamyl-benzoate

A solution of ethyl-3-allylamino-4-phenoxy-5-suplphamyl-benzoate (1.65g) in ethanol (150 ml) was hydrogenated at room temperature and 1.1atmospheres hydrogen pressure after the addition of apalladium-on-carbon catalyst (0.6 g catalyst containing 10% Pd). Afterthe hydrogen uptake had become negligible, the catalyst was removed byfiltration, and the filtrate was evaporated in vacuo. The residue wasrecrystallized twice from aqueous ethanol, resulting inethyl-4-phenoxy-3-n-propylamino-5-sulphamyl-benzoate with a meltingpoint of 150°-151°C.

B. 4-phenoxy-3-n-propylamino-5-sulphamyl-benzoic acid

Ethyl-4-phenoxy-3-n-propylamino-5-sulphamyl-benzoate (1 g) was dissolvedin 1N sodium hydroxide (15 ml), and heated on a steam bath for 1 hour.After cooling, the 4-phenoxy-3-n-propylamino-5-sulphamyl-benzoic acidwas precipitated by addition of 4N hydrochloric acid until the pH was2.5; the melting point was 223°-224°C.

EXAMPLE 61 3-Ethylamino-4-phenoxy-5-sulphamyl-benzoic acid

A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (3.08 g), ethyliodide (20 ml), and ethanol (20 ml) was refluxed for 6 days. Aftercooling, the reaction mixture was evaported to dryness, and the residuewas washed with a little ethanol followed by diethyl ether. The ethyl3-ethylamino-4-phenoxy-5-sulphamyl-benzoate obtained was dissolved in 1Nsodium hydroxide (35 ml) and heated on a steam bath for 30 minutes.After cooling, the reaction mixture was adjusted to pH 2.5 by additionof 4N hydrochloric acid, and the precipitated3-ethylamino-4-phenoxy-5-sulphamyl-benzoic acid was isolated byfiltration. After recrystallization from ethanol and drying in vacuo at115°C, the compound was obtained with a melting point of 236°-237°C.

EXAMPLE 62 3-n-Pentylamino-4-phenoxy-5-sulphamyl-benzoic acid

A. n-Pentyl-3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoate

A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (6 g),n-pentanol (60 ml), and conc. sulphuric acid (0.5 ml) was refluxed for24 hours. After cooling, the precipitated n-pentyl3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoate was isolated byfiltration and recrystallized from n-pentanol. After drying in vacuo,the compound was obtained with a melting point of 138°-139°C.

B. 3-n-Pentylamino-4-phenoxy-5-sulphamyl-benzoic acid

A mixture of n-pentyl 3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoate(4.5 g) and 1N sodium hydroxide (70 ml) was heated on a steam bath for 1hour. After cooling, the reaction mixture was adjusted to a pH of 2.5 byaddition of 4N hydrochloric acid. The precipitated3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoic acid was isolated byfiltration and recrystallized from aqueous ethanol. After drying invacuo, the compound was obtained with a melting point of 223°-224°C.

EXAMPLE 63 3-Benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid

A. ethyl 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoate

A mixture of 3-amino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid (4g), benzyl bromide (4.1 g), and ethanol (60 ml) was refluxed for 4hours. After cooling, the precipitated ethyl3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoate was isolatedby filtration and recrystallized from ethanol. The compound was obtainedwith a melting point of 166°C.

B. 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid

A solution of ethyl3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoate (2 g) in 1Nsodium hydroxide (45 ml) was left standing at room temperature for 40hours. Then the reaction mixture was adjusted to a pH of 2.5 by additionof 4N hydrochloric acid. The precipitated3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid wasisolated by filtration and recrystallized from aqueous ethanol. Afterdrying, the compound was obtained with a melting point of 249°-251°C.

EXAMPLE 64 3-Benzylamino-4-(4-hydroxyphenoxy)-5-sulphamyl-benzoic acid

A suspension of 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoicacid (0.5 g) in water (5 ml) was adjusted to a pH of 11 by addition of1N sodium hydroxide. The resulting soluton was hydrogenated at roomtemperature and 1.1 atmospheres hydrogen pressure after addition ofPd-on-carbon powder catalyst (0.025 g catalyst containing 10% of Pd).After the hydrogen uptake had become negligible, the catalyst wasremoved by filtration, and from the filtrate the3-benzylamino-4-(4-hydroxyphenoxy)-5-sulphamyl-benzoic acid wasprecipitated by addition of 4N hyrochloric acid until a pH of 2. Afterisolation by filtration and recrystallization from aqueous ethanol, thecompound was obtained with a melting point of 276-277°C (decomp.).

EXAMPLE 65 3-Furfurylamino-4-phenoxy-5-sulphamyl-benzoic acid and itssodium salt

A. sodium salt of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid

A suspension of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (10 g) inwater (25 ml) was adjusted to a pH of 8 by addition of 1N sodiumhydroxide at 80°C. After cooling, the precipitated sodium salt wascollected by suction and dried in vacuo at 115°C.

B. sodium salt of 3-furfurylamino-4-phenoxy-5-sulphamyl-benzoic acid

A mixture of the sodium salt of 3-amino-4-phenoxy-5-sulphamyl-benzoicacid (5 g), furfural (2.2 g), and methanol (75 ml) was refluxed for 5hours. Then the reaction mixture was cooled to 0°C and sodiumborohydride, NaBH₄, (2.2 g) was added in portions during 1 hour, whilestirring and keeping the temperature at 0-5°C. After standing for 16hours, the solvent was distilled off in vacuo, and the residue wasdissolved in water (45 ml). The solution was adjusted to a pH of 7.5 byaddition of 4N hydrochloric acid and cooled. The precipitated sodiumsalt of 3-furfurylamino-4-phenoxy-5-sulphamyl-benzoic acid was collectedby suction, recrystallized from water, and dried.

C. 3-furfurylamino-4-phenoxy-5-sulphamyl-benzoic acid

The sodium salt of 3-furfurylamino-4-phenoxy-5-sulphamyl-benzoic acid (1g) was dissolved in water (50 ml) at 50°C and acetic acid (1 ml) wasadded dropwise, while stirring. After cooling, the precipitated acid wascollected by suction and recrystallized from aqueous ethanol. Themelting point was 219°-220°C.

EXAMPLE 66 3,4-Dibenzylamino-5-sulphamyl-benzoic acid, and its sodiumsalt

A suspension of 3-anmino-4-benzylamino-5-sulphamyl-benzoic acid (1 g) inwater (20 ml) was adjusted to a pH of 7.5 by addition of 1N sodiumhydroxide. To the solution benzyl bromide (0.54 g) was added and, whilestirring, the pH was kept at 7.5 by automatic titration with sodiumhydroxide. After the base consumption had become negligible, theprecipitated sodium salt of 3,4-dibenzylamino-5-sulphamyl-benzoic acidwas collected by suction and washed with a little water. The sodium saltwas dissolved in aqueous ethanol (62 ml containing 25% of ethanol), andthe acid was precipitated by addition of acetic acid (2 ml). The acidwas collected by suction and dried, the melting pont was 205°C.

EXAMPLE 67 3-Benzylamino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid

A mixture of 3-amino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid(3.35 g), benzyl bromide (5.3 g), and anhydrous ethanol (30 ml) wasrefluxed for 48 hours. After cooling, the precipitated ethyl ester wascollected by suction, recrystallized from ethanol and saponified byheating in 1N sodium hydroxide (30 ml) for 1 hour. The3-benzylamino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid wasprecipitated at room temperature by addition of 4N hydrochloric aciduntil the pH was 2.5. After recrystallization from aqueous ethanol, thecompound was obtained with a melting point of 203°C.

EXAMPLE 68 3-Benzylamino-4-piperidino-5-sulphamyl-benzoic acid

A mixture of 3-amino-4-piperidino-5-sulphamyl-benzoic acid (2.5 g),benzyl bromide (1.4 g), and dry ethanol (30 ml) was refluxed for 3 days.The reaction mixture was evaporated in vacuo, and the residue was washedwith petroleum ether. The crude ethyl3-benzyl-amino-4-piperidino-5-sulphamyl-benzoate obtained was saponifiedby addition of 1N sodium hydroxide and heated on a steam bath for 1hour. After cooling and adjusting the pH to 4 by means of 4Nhydrochloric acid, 3-benzylamino-4-piperidino-5-sulphamyl-benzoic acidprecipitated. After collecting and recrystallizing from aqueous ethanol,the compound was obtained as a hemi-hydrate with a melting point of195°C.

EXAMPLE 69 3-Benzylamino-4-isopropylamino-5-sulphamyl-benzoic acid

A mixture of 3-amino-4-isopropylamino-5-sulphamyl-benzoic acid (2.62 g),benzyl bromide (4.28 g), and anhydrous ethanol (25 ml) was refluxed for24 hours. The reaction mixture was evaporated in vacuo. 1N sodiumhydroxide (30 ml) was added, and the mixture was heated on a steam bathfor 1 hour. After cooling and extracting with diethyl ether, the aqueouslayer was adjusted to a pH of 3 by addition of 4N hydrochloric acid. Theprecipitated 3-benzylamino-4-isopropylamino-5-sulphamyl-benzoic acid wascollected by suction and recrystallized from aqueous ethanol. Themelting point was 233°-234°C.

EXAMPLE 70 3-Benzylamino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoicacid

A suspension of 3-amino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoicacid (0.5 g) in water (25 ml) was adjusted to a pH of 8 by addition of1n lithium hydroxide. To the resulting solution, benzyl bromide (0.2 g)was added while, under stirring, the pH was kept at 8 by automatictitration with 1N lithium hydroxide. After the base consumpton hadbecome negligible, the crude3-benzylamino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid wasprecipitated from the reaction mixture by adjusting the pH to 5 by meansof 1N hydrochloric acid. The compound was collected by suction,recrystallized from aqueous ethanol, and dried. The melting point of thecompound was 168°-170°C.

EXAMPLE 71 Ethyl3-benzylamino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoate

A mixture of 3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoicacid (1.82 g), benzyl bromide (2 g), and anhydrous ethanol (15 ml) wasrefluxed for 7 hours. The soluton was cooled, and the precipitated ethyl3-benzylamino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoate wascollected by suction. After recrystallization from ethanol, the meltingpont was 166°-168°C.

Ethyl 3-benzylamino-4-(p-methoxyanilino)-5-sulphamyl-benzoate

By substituting 3-amino-4-(p-methoxyanilino)-5-sulphamyl-benzoic acid(1.69 g) for the3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid andextending the heating time to 20 hours, the above compound was obtainedwith a melting point of 145°C.

Ethyl 3-benzylamino-4-(m-methoxyanilino)-5-sulphamyl-benzoate

By substituting 3-amino-4-(m-methoxyanilino)-5-sulphamyl-benzoic acid(1.69 g) for the3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid andextending the heating time to 20 hours, the above comound was obtainedwith a melting point of 149°-152°C.

Ethyl 3-benzylamino-4-(p-methoxyphenoxy)-5-sulphamyl-benzoate

By substituting 3-amino-4-(p-methoxyphenoxy)-5-sulphamyl-benzoic acid(1.69 g) for the3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid, the abovecompound was obtained as a precipitate during the heating time. Aftercollection by suction and recrystallizing from acetone, the compound hada melting point of 189°-190°C.

Ethyl 3-benzylamino-4-cyclohexylamino-5-sulphamyl-benzoate

By substituting 3-amino-4-cyclohexylamino-5-sulphamyl-benzoic acid (1.5g) for the 3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acidand adding water (13 ml) to the cooled reaction mixture, the abovecompound was obtained with a melting point of 176°-177°C.

Ethyl 3-benzylamino-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoate

By substituting 3-amino-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoicacid (1.8 g) for the3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid andincreasing the amount of ethanol to 50 ml, the above compound wasobtained with a melting point of 189°-190°C.

Ethyl 3-benzylamino-4-(β-naphthylamino)-5-sulphamyl-benzoate

By substituting 3-amino-4-(β-naphthylamino)-5-sulphamyl-benzoic acid(1.8 g) for the 3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoicacid and increasing the amount of ethanol to 25 ml, the above compoundwas obtained with a melting point of 199°-201°C.

EXAMPLE 72 Ethyl 3-benzylamino-5-sulphamyl-4-(m-toluidino)-benzoate

A mixture of 3-amino-5-sulphamyl-4-(m-toluidino)-benzoic acid (1.5 g),benzyl bromide (2.5 g), and anhydrous ethanol (50 ml) was heated underreflux for 10 hours. The resulting solution was cooled, and theprecipitated ethyl 3-benzylamino-5-sulphamyl-4-(m-toluidino)-benzoatewas collected by suction. After recrystallization from ethanol, thecompound had a melting point of 169-170°C.

Ethyl 3-benzylamino-5-sulphamyl-4-(p-toluidino)-benzoate

By substituting 3-amino-5-sulphamyl-4-(p-toluidino)-benzoic acid for the3-amino-5-sulphamyl-4-(m-toluidino)-benzoic acid, the above compound wasobtained with a melting point of 159-160°C.

Ethyl 3-benzylamino-4-(p-chloroanilino)-5-sulphamyl-benzoate

By substituting 3-amino-4-(p-chloroanilino)-5-sulphamyl-benzoic acid (2g) for the 3-amino-5-sulphamyl-4-(m-toluidino)-benzoic acid, the abovecompound was obtained with a melting point of 187°C.

Ethyl 3-benzylamino-4-(2,4-dimethylanilino)-5-sulphamyl-benzoate

By substituting 3-amino-4-(2,4-dimethylanilino)-5-sulphamyl-benzoic acid(2 g) for the 3-amino-5-sulphamyl-4-(m-toluidino)-benzoic acid, theabove compound was obtained with a melting point of 167-168°C.

EXAMPLE 73 Ethyl 3-benzylamino-4-n-(butylthio)-5-sulphamyl-benzoate

A mixture of 3-amino-4-(n-butylthio)-5-sulphamyl-benzoic acid (1.5 g),benzyl bromide (2.1 g), and anhydrous ethanol, (20 ml) was refluxed for24 hours. After the first 7 hours of refluxing, benzyl bromide (0.7 g)was added. After cooling, the precipitated ethyl3-benzylamino-4-(n-butylthio)-5-sulphamyl-benzoate was collected andrecrystallized from ethanol, after which the compound was obtained witha melting point of 151-157°C.

Ethyl 3-benzylamino-4-(p-carbethoxyanilino)-5-sulphamyl-benzoate

By substituting 3-amino-4-(p-carboxyanilino)-5-sulphamyl-benzoic acid(1.7 g) for the 3-amino-4-(n-butylthio)-5-sulphamyl-benzoic acid, theabove compound was obtained with a melting point of 161°C.

EXAMPLE 74 Ethyl 3-benzylamino-4-morpholino-5-sulphamyl-benzoate

A mixture of 3-amino-4-morpholino-5-sulphamyl-benzoic acid (3 g), benzylbromide (4 g), and anhydrous ethanol (45 ml) was refluxed. After 24hours and again after 48 hours a solution of benzyl bromide (1.5 g) inanhydrous ethanol (5 ml) was added during 4 hours. After the secondaddition, the refluxing was continued for 24 hours. The reaction mixturewas cooled, and the precipitated ethyl3-benzylamino-4-morpholino-5-sulphamyl-benzoate was collected by suctionand recrystallized from ethanol, after which the compound was obtainedwith a melting point of 185-186°C.

Ethyl 3-benzylamino-5-sulphamyl-4-(o-tolylthio)-benzoate

By substituting 3-amino-5-sulphamyl-4-(o-tolylthio)-benzoic acid for the3-amino-4-morpholino-5-sulphamyl-benzoic acid, the above compound wasobtained with a melting point of 166-167°C.

EXAMPLE 75 Ethyl 3-benzylamino-5-sulphamyl-4-(β,β,β-trifluoroethoxy)-benzoate

A mixture of 3-amino-5-sulphamyl-4-(β, β, β-trifluoroethoxy)-benzoicacid (0.6 g), benzyl bromide (1.2 g), and dry ethanol (8 ml) wasrefluxed for 5 hours. After cooling, the precipitated ethyl3-benzylamino-5-sulphamyl-4-(β, β, β-trifluoroethoxy)-benzoate wascollected by suction and recrystallized from dry ethanol. After drying,the compound had a melting point of 163-165°C.

EXAMPLE 76 4-Substituted 3-benzylamino-5-sulphamyl-benzoic acids bysaponification of the corresponding ethyl esters

General procedure:

The corresponding ethyl ester (2 g), prepared as in Examples 71 to 75,was dissolved in 1N sodium hydroxide (30 ml) and heated on a steam bathfor 1 hour. After cooling, the acid was precipitated by addition of 4Nhydrochloric acid, until the pH was 2.5, collected by suction,recrystallized from aqueous ethanol, and dried at 115°C in vacuo.

The following acids were obtained:

3-Benzylamino-5-sulphamyl-4-(m-toluidino)-benzoic acid with a meltingpoint of 226-227°C.

3-benzylamino-5-sulphamyl-4-(p-toluidino)-benzoic acid with a meltingpoint of 217-218°C.

3-benzylamino-4-(p-methoxyanilino)-5-sulphamyl-benzoic acid with amelting point of 207-208°C.

3-benzylamino-5-sulphamyl-4-(m-trifluoromethylanilino)-benzoic acid witha melting point of 227-228°C after recrystallization from isopropanol.

3-Benzylamino-4-(p-chloroanilino)-5-sulphamyl-benzoic acid with amelting point of 245-246°C.

3-benzylamino-4-(2,4-dimethylanilino)-5-sulphamyl-benzoic acid with amelting point of 245-246°C

3-benzylamino-4-(p-carboxyanilino)-5-sulphamyl-benzoic acid preparedfrom ethyl 3-benzylamino-4-(p-carbethoxyanilino)-5-sulphamyl-benzoicacid and precipitated at a pH of 1.5 with a melting point higher than300°C and containing one-half molecule of water of crystallization.

3-Benzylamino-5-sulphamyl-4-(o-tolylthio)-benzoic acid with a meltingpoint of 227-228°C.

3-benzylamino-4-(p-methoxyphenoxy)-5-sulphamyl-benzoic acid with amelting point of 230-232°C.

3-benzylamino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid witha melting point of 220-222°C.

3-benzylamino-4-(β-naphthylamino)-5-sulphamyl-benzoic acid with amelting point of 261-263°C.

3-benzylamino-4-cyclohexylamino-5-sulphamyl-benzoic acid with a meltingpoint of 249-250°C.

3-benzylamino-4-morpholino-5-sulphamyl-benzoic acid with a melting pointof 237°C.

3-benzylamino-4-(n-butylthio)-5-sulphamyl-benzoic acid with a meltingpoint of 210-211°C.

3-benzylamino-5-sulphamyl-4-(β,β,β-trifluoroethoxy)-benzoic acid with amelting point of 230-232°C.

EXAMPLE 77 4-Anilino-3-butylamino-5-sulphamyl-benzoic acid

A mixture of 3-amino-4-anilino-5-sulphamyl-benzoic acid (4 g), n-butanol(50 ml), and conc. H₂ SO₄ (0.4 ml) was boiled under reflux with waterseparator for 5 days. The resulting solution of butyl4-anilino-3-butylamino-5-sulphamyl-benzoate was saponified by additionof 2N sodium hydroxide and boiling under reflux for 45 minutes. Afterneutralization with 4N hydrochloric acid, the reaction mixture wasevaporated in vacuo. The residue was dissolved in hot water (50 ml), andthe 4-anilino-3-butylamino-5-sulphamyl-benzoic acid was precipitated byaddition of 4N hydrochloric acid to pH 3. The crude acid was dissolvedin diethyl ether (50 ml), and undissolved impurities were filtered off.The etherial solution was evaporated to dryness, and the residue wasrecrystallized from acetone-water and aqueous ethanol, after which thecompound was obtained with a melting point of 230-231°C.

EXAMPLE 78 3-Benzylamino-4-butylamino-5-sulphamyl-benzoic acid

A. 4-butylamino-3-nitro-5-sulphamyl-benzoic acid

A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (8.4 g),n-butylamine (8.7 g), and water (25 ml) was stirred at 90°C for 1.5hours. After cooling, the pH was adjusted to pH 2, and the precipitated4-butylamino-3-nitro-5-sulphamyl-benzoic acid was collected byfiltration. After several recrystallizations from aqueous methanol themelting point was 192.5°C.

B. 3-amino-4-butylamino-5-sulphamyl-benzoic acid

A suspension of 4-butylamino-3-nitro-5-sulphamyl-benzoic acid (8.6 g) inwater (175 ml) was adjusted to pH 9.5 by addition of 2N sodiumhydroxide. The resulting solution was hydrogenated after addition ofPd-on-carbon catalyst (0.5 g catalyst containing 10% Pd). After thehydrogen uptake had become negligible, the catalyst was removed byfiltration, and the 3-amino-4-butylamino-5-sulphamyl-benzoic acid wasprecipitated from the filtrate by addition of 4N hydrochloric acid untilpH 3. After recrystallization from aqueous methanol the melting pointwas 211-211.5°C.

C. 3-benzylamino-4-butylamino-5-sulphamyl-benzoic acid

A suspension of 3-amino-4-butylamino-5-sulphamyl-benzoic acid (6.5 g) inwater (30 ml) was adjusted to pH 7.5 H by addition of 1N sodiumhydroxide. Benzyl bromide (3.87 g) was added and, under stirring, the pHwas kept at pH 7.5 by automatic titration with 1N sodium hydroxide.After the base consumption had become negligible, the pH was adjusted to3 by addition of diluted hydrochloric acid. The precipitated3-benzylamino-4-butylamino-5-sulphamyl-benzoic acid was collected andrecrystallized several times from aqueous methanol, after which thecompound was obtained with a melting point of 198.5-199°C.

EXAMPLE 79 5-Acetylsulphamyl-3-benzylamino-4-phenoxy-benzoic acid

A mixture of 3-amino-5-acetylsulphamyl-4-phenoxy-benzoic acid (1 g),benzaldehyde (0.3 g), and acetic acid (40 ml) was heated on a steam bathfor 2 hours. After cooling to room temperature, platinum oxide catalyst(0.035 mg) was added, and the reaction mixture was hydrogenated at roomtemperature and at 1.1 atmospheres hydrogen pressure. After the hydrogenuptake had become negligible, the catalyst was removed by filtration,and the filtrate evaporated in vacuo. After several recrystallizationsof the residue from aqueous ethanol, and after drying in vacuo at 76°C,the compound was obtained with a melting point of 241-243°C. Thecompound crystallized as a hemi-hydrate.

EXAMPLE 80 3-Benzylamino-4-phenoxy-5-sulphamyl-benzoic acid

A mixture of 5-acetylsulphamyl-3-benzylamino-4-phenoxy-benzoic acid (1g), ethanol (20 ml), and 4N hydrochloric acid (5 ml) was refluxed for2.5 hours. Then 2N sodium hydroxide (15 m1) was added, and the reactionmixture was heated on a steam bath for 30 minutes. After cooling, the pHwas adjusted to 2.5 by addition of 4N hydrochloric acid, and theprecipitated 3-benzylmino-4-phenoxy-5-sulphamyl-benzoic acid wasisolated by filtration. After recrystallization from aqueous ethanol anddrying, the compound was obtained with a melting point of 264-265°C.

EXAMPLE 81 3-Benzylamino-5-methylsulphamyl-4-phenoxy-benzoic acid

A. ethyl 3-benzylamino-5-methylsulphamyl-4-phenoxy-benzoate

A mixture of 3-amino-5-methylsulphamyl-4-phenoxy-benzoic acid (1 g),benzyl bromide (1.25 g), and dry ethanol (15 ml) was refluxed for 9hours. After 3 hours and after 6 hours more benzyl bromide (0.6 g) wasadded. After cooling, the precipitated ethyl3-benzylamino-5-methylsulphamyl-4-phenoxy-benzoate was collected bysuction, recrystallized from ethanol, and dried in vacuo. The meltingpoint of the compound was 162.5°C.

B. 3-benzylamino-5-methylsulphamyl-4-phenoxy-benzoic acid

Ethyl 3-benzylamino-5-methylsulphamyl-4-phenoxy-benzoate (0.5 g) wasdissolved in 1N sodium hydroxide (8 ml) and heated on a steam bath for 1hour. After cooling, the3-benzylamino-5-methylsulphamyl-4-phenoxy-benzoic acid was precipitatedby addition of 4N hydrochloric acid until a pH of 2.5. The precipitatewas collected by suction and recrystallized from aqueous ethanol. Afterdrying in vacuo, the melting point of the compound was 231-233°C.

EXAMPLE 82 3-Benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoic acid

A. ethyl 3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoate

A mixture of 3-amino-5-dimethylsulphamyl-4-phenoxy-benzoic acid (1.68g), benzyl bromide (2 g), and ethanol (15 ml) was refluxed for 5 hours.After cooling, the precipitated ethyl3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoate was isolated andrecrystallized from ethanol. After drying in vacuo, the compound wasobtained with a melting point of 154-155°C.

B. 3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoic acid

Ethyl 3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoate (1 g) washeated on a steam bath with 1N sodium hydroxide (15 ml) for 6 hours.From the resulting solution, the3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoic acid wasprecipitated by addition of 4N hydrochloric acid until a pH of 2.5.After isolating and recrystallizing from aqueous ethanol, the compoundwas obtained with a melting point of 205-206°C.

Ethyl 3-benzylamino-5-(n-butylsulphamyl)-4-phenoxy-benzoate

By substituting in step A above3-amino-5-butylsulphamyl-4-phenoxy-benzoic acid (1.8 g) for the3-amino-5-dimethylsulphamyl-4-phenoxy-benzoic acid, the above compoundwas obtained with a melting point of 149-149.5°C.

3-Benzylamino-5-(n-butylsulphamyl)-4-phenoxy-benzoic acid

By substituting in step B above ethyl3-benzylamino-5-(n-butylsulphamyl)-4-phenoxy-benzoate for the ethyl3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoate, and afterrecrystallization from ethanol, the aove compound was obtained with amelting point of 212°C.

EXAMPLE 83 3-Butylamino-5-(n-butylsulphamyl)-4-phenoxy-benzoic acid

3-Amino-5-(n-butylsulphamyl)-4-phenoxy-benzoic acid was substituted forthe 3-amino-4-phenoxy-5-sulphamyl-benzoic acid of Example 41. After thesaponification, the organic solvents were removed from the reactionmixture by azeotropic distillation. The obtained aqueous solution wasadjusted to pH 2.5 by addition of 4N hydrochloric acid. The precipitated3-(n-butylamino)-5-(n-butylsulphamyl)-4-phenoxy-benzoic acid wasisolated by filtration and was several times recrystallized from aqueousethanol. After drying in vacuo at 115°C, the compound had a meltingpoint of 184-185°C.

EXAMPLE 84 4-Anilino-3-benzylamino-5-phenylsulphamyl-benzoic acid

A. ethyl 4-anilino-3-benzylamino-5-phenylsulphamyl-benzoate

By substituting 3-amino-4-anilino-5-phenylsulphamyl-benzoic acid (1.8 g)for the 3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid ofExample 71, the above compound was obtained with a melting point of165°C.

B. 4-anilino-3-benzylamino-5-phenylsulphamyl-benzoic acid

Ethyl 4-anilino-3-benzylamino-5-phenylsulphamyl-benzoate (3 g) wasdissolved in 1N sodium hydroxide (35 ml), and the solution was heated ona steam bath for 1 hour. After cooling, the reaction mixture wasadjusted to a pH of 2.5 by addition of 4N hydrochloric acid. Theprecipitated 4-anilino-3-benzylamino-5-phenylxulphamyl-benzoic acid wascollected by suction and recrystallized from acetone/water. The compoundwas obtained with a melting point of 243°C.

What I claim is:
 1. A compound of the formula ##SPC5##in which A is R²-- S --, R², R³, and R⁴ are saturated or unsaturated aliphatichydrocarbon radicals having from 1 to 7 carbon atoms, cycloalkyl andcycloalkenyl radicals having from 3-8 carbon atoms, phenyl-lower alkylradicals having from 7 to 10 carbon atoms or cycloalkyl -- lower alkylradicals having from 4 to 12 carbon atoms, R² and R³ may also be mono-or bi-cyclic carbocyclic aryl radicals, R⁵ is a lower alkyl radical, R⁶is a lower alkyl radical or a lower alkanoyl groups, R³, R⁴, R⁵ and R⁶may also be a hydrogen atom, R² may also be substituted with chlorine,fluorine, methyl, trifluoromethyl, carboxy, carbethoxy, dimethyl amino,hydroxy, methoxy, benzyloxy, or sulfamyl groups and R⁴ may besubstituted with chlorine, methyl, and methoxy groups; pharmaceuticallyacceptable salts thereof, and esters thereof with lower alkanols,phenol, cyanomethanol or benzyl alcohol. 2.3-n-Butylamino-4-phenyl-thio-5-sulfamyl-benzoic acid, a pharmaceuticallyacceptable salt thereof or an ester thereof with a lower alkanol,phenol, cyanomethanol or benzyl alcohol. 3.3-Benzylamino-4-phenylthio-5-sulfamyl-benzoic acid, a pharmaceuticallyacceptable salt thereof or an ester thereof with a lower alkanol,phenol, cyanomethanol or benzyl alcohol.